@article {pmid42863362,
year = {2026},
author = {Zhou, Z},
title = {Uncovering the mechanism of gastrodin in treating Alzheimer's disease through bioinformatics, machine learning, and virtual gene knockout technology.},
journal = {Computational biology and chemistry},
volume = {126},
number = {Pt 2},
pages = {109464},
doi = {10.1016/j.compbiolchem.2026.109464},
pmid = {42863362},
issn = {1476-928X},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Gastrodin is a natural compound with neuroprotective activity; however, the precise molecular mechanisms underlying its therapeutic effects on human AD remain unclear. This study employed bioinformatics approaches to systematically elucidate the therapeutic mechanisms of gastrodin in AD. Pharmacokinetic analysis showed that gastrodin exhibited favorable drug-like properties (bioavailability score: 0.55; LogP: -0.85) and an acceptable overall toxicity profile, although predicted nephrotoxicity (0.71) and ototoxicity (0.908) scores suggest potential safety concerns warranting further investigation. Next, differentially expressed genes (DEGs) associated with AD were screened from GEO datasets, yielding 13 core targets that overlapped with gastrodin-responsive genes. Functional enrichment analysis indicated significant enrichment of these targets in signaling pathways closely related to neuroinflammation and cell survival, including the Ras-proximate 1 (Rap1), Ras, mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) pathways. The Ridge model achieved AUCs of 0.898 in the training set and 0.859 in the GSE37263 cohort, but showed modest generalizability in the GSE138260 cohort (AUC = 0.684), highlighting the heterogeneity of external datasets. Further single-cell transcriptomic analysis revealed specific upregulation of insulin-like growth factor 1 receptor (IGF1R) in brain endothelial cells of AD patients. Virtual gene knockout simulations demonstrated that IGF1R knockout substantially disrupted core networks associated with endothelial functions and neurovascular homeostasis, including focal adhesion and calcium signaling pathways. Finally, molecular docking and molecular dynamics (MD) simulations revealed stable binding conformations of gastrodin to EGFR and MET, while the gastrodin-IGF1R complex exhibited a more dynamic binding behavior with conformational flexibility, suggesting an induced-fit binding mechanism. MM/PBSA calculations revealed favorable enthalpic contributions (ΔH = -17.43, -13.63, and -10.41 kcal/mol for EGFR, IGF1R, and MET, respectively) for gastrodin-target binding. In conclusion, this study suggests that gastrodin exerts multi-target effects via coordinated regulation of multiple signaling pathways. Notably, gastrodin targets IGF1R in brain endothelial cells, modulating focal adhesion/calcium signaling networks, thus providing a novel mechanistic hypothesis for AD treatment by restoring neurovascular unit homeostasis.},
}

@article {pmid42863691,
year = {2026},
author = {Urano, Y and Maeda, W and Noguchi, N},
title = {Inhibition of glycan sialylation reduces amyloid-β secretion via suppression of amyloid-β exocytosis.},
journal = {Biochimie},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.biochi.2026.10.016},
pmid = {42863691},
issn = {1638-6183},
abstract = {Among nutrient-sensitive regulatory mechanisms, protein glycosylation is a key post-translational modification that links metabolism to protein function. Amyloid-β (Aβ) peptides play a crucial role in the pathogenesis of Alzheimer's disease (AD). Because excessive accumulation of Aβ is believed to drive AD progression, approaches that reduce Aβ production and secretion remain of considerable therapeutic interest. Accumulating evidence suggests that protein glycosylation influences the processing and trafficking of amyloid-β precursor protein (APP) and other proteins involved in Aβ metabolism. However, while N-linked protein glycosylation has been shown to affect Aβ production, the specific contribution of protein terminal glycan sialylation remains incompletely understood. In this study, we investigated the effects of inhibiting glycan sialylation on Aβ production using CHO cells stably expressing human APP. Treatment with the sialyltransferase inhibitor P-3Fax-Neu5Ac (P-3Fax) significantly reduced extracellular Aβ levels, while intracellular Aβ levels were increased. Importantly, P-3Fax treatment did not alter β-secretase- or γ-secretase-mediated cleavage of their substrates, indicating that changes in secretase activity do not account for the reduction in extracellular Aβ. In addition, P-3Fax treatment markedly reduced plasma membrane levels of lysosome-associated membrane protein 1 (LAMP1), consistent with impaired lysosomal exocytosis. Taken together, these results indicate that inhibition of sialylation by P-3Fax reduces extracellular Aβ levels independently of secretase activity, potentially through impaired lysosomal exocytotic pathways. Our findings identify glycan sialylation as a key regulatory factor in Aβ trafficking and provide new insight into the cellular mechanisms controlling Aβ homeostasis.},
}

@article {pmid42863694,
year = {2026},
author = {Tanahashi, M and Kozuka, A and Sasakawa, N and Niikura, T},
title = {Humanin attenuates neuronal cellular senescence and preserves neurotransmitter release in differentiated PC12 cells.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.10.017},
pmid = {42863694},
issn = {1873-7544},
abstract = {Cellular senescence, characterized as a permanent arrest of cell proliferation, is triggered by various types of stress. Senescent cells are identified by markers, including senescence-associated β-galactosidase (SA-β-gal) activity and the secretion of senescence-associated secretory phenotype (SASP) factors. These senescent phenotypes have been observed in neurons, suggesting that cellular senescence may contribute to the pathogenesis of neurodegenerative diseases. Humanin (HN), an endogenous short peptide, mitigates Alzheimer's disease-associated pathologies, including amyloid β-induced neuronal cell death. Overexpression of HN extends the lifespan of nematodes, suggesting a potential anti-aging role for this peptide. Here, we first investigated the effect of HN on cellular senescence in mouse primary cortical neurons. Chronic treatment with HNG, a highly potent HN derivative, attenuated prolonged culture-induced senescence. To further determine whether this anti-senescent effect is associated with preserved exocytotic function, we employed a glutamate-induced senescence model in neuronal-differentiated PC12 cells. In this system, HNG mitigated changes in senescence-associated markers, including increases in SA-β-gal activity, Ki67 expression, and SASP factor expression. In addition, acetylcholine-induced dopamine release was reduced in senescent PC12 cells, whereas chronic HN treatment sustained the expression levels of synapsin 1 and synaptophysin and attenuated the senescence-associated decrease in neurotransmitter release. These findings suggest that HN suppresses senescence and sustains exocytosis activity in neuronal cells, supporting an anti-aging function of HN at the cellular level.},
}

@article {pmid42863728,
year = {2026},
author = {Li, Y and Tang, ZL and Liu, FW and Chen, M and Chang, SQ and Ding, FM and Bian, QL and Pan, JP and Qiu, ZC and Kong, MW and Li, Y and Chen, JX},
title = {Si-Shen-San Attenuates Alzheimer's Disease Pathology and Cognitive Deficits Through Multi-Target Regulation of Astrocyte Function and Synaptic Plasticity.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122475},
doi = {10.1016/j.jep.2026.122475},
pmid = {42863728},
issn = {1872-7573},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by cognitive decline, amyloid-β (Aβ) deposition, tau hyperphosphorylation, synaptic dysfunction, and astrocyte dysregulation. The constituent herbs of the traditional Chinese medicine formula Si-Shen-San (SSS) have been used to ameliorate cognitive impairment. However, the comprehensive chemical profile, core bioactive constituents, and underlying mechanisms of action of SSS remain to be fully elucidated.

AIM OF THE STUDY: This study aims to systematically investigate the therapeutic potential of SSS against AD and to clarify its multi-faceted mechanisms of action, with a focus on astrocyte-mediated neuroprotection, synaptic repair, and modulation of core AD pathologies.

MATERIALS AND METHODS: Ultra-high performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UHPLC-Q/TOF-MS) was used to characterize the chemical constituents of SSS extract and SSS-containing serum. In vivo, 3×Tg-AD mice were orally administered SSS. And cognitive function, AD-related pathology, synaptic integrity, and astrocyte-associated molecular changes were evaluated using behavioral, histological, biochemical, ultrastructural, and electrophysiological approaches. In vitro, an astrocyte-conditioned medium paradigm was used to examine whether SSS-induced changes in astrocytes were associated with protection of HT22 neurons against glutamate-induced injury.

RESULTS: UHPLC-Q/TOF-MS tentatively annotated 525 and 318 compounds in the SSS extract and drug-containing serum. In 3×Tg-AD mice, SSS improved cognitive performance, reduced hippocampal 6E10- and ThS-positive Aβ-like immunoreactivity and tau phosphorylation at Thr231 and Ser404, and preserved synaptic structure and function. The reduction in tau phosphorylation was accompanied by changes in GSK-3β signaling. SSS treatment was also associated with reduced astrocyte reactivity, increased GLT-1 expression, and restoration of astrocyte-associated homeostatic markers. In vitro, conditioned medium derived from SSS-treated C8-D1A astrocytes alleviated glutamate-induced injury in HT22 neurons and was accompanied by activation of neuronal CREB-BDNF signaling.

CONCLUSION: SSS ameliorated cognitive deficits and multiple AD-related pathological alterations in 3×Tg-AD mice. These effects were associated with restoration of astrocyte-related homeostatic features, improved glutamate regulation, preservation of synaptic integrity, and activation of CREB-BDNF signaling. These findings provide an experimental foundation for SSS as a potential therapeutic strategy for AD and highlight astrocyte homeostasis as a promising target for future drug development.},
}

@article {pmid42865133,
year = {2026},
author = {Lv, Y and Shi, M and Zhao, Y and Yu, Y and Lv, J and Zhao, H},
title = {Context-dependent TREM2 signalling in myeloid cells: Molecular mechanisms and immunotherapeutic divergence in neurodegeneration and cancer.},
journal = {Clinical and translational medicine},
volume = {16},
number = {10},
pages = {e70863},
pmid = {42865133},
issn = {2001-1326},
support = {ZR2022QH372//Shandong Province Natural Science Foundation/ ; },
mesh = {Humans ; *Receptors, Immunologic/metabolism ; *Membrane Glycoproteins/metabolism ; *Signal Transduction ; *Myeloid Cells/metabolism/immunology ; *Neoplasms/therapy/immunology ; Animals ; *Immunotherapy/methods ; *Neurodegenerative Diseases/therapy/immunology ; },
abstract = {BACKGROUND: Triggering receptor expressed on myeloid cells 2 (TREM2) is a pivotal lipid-sensing receptor that governs the functional plasticity and metabolic fitness of mononuclear phagocytes, including microglia, osteoclasts, dendritic cells and tissue-resident macrophages. While originally identified as a genetic risk factor for Alzheimer's disease (AD), TREM2 functions as a context-dependent immunometabolic checkpoint rather than a uniform phenotypic driver, exerting divergent biological outputs dictated by distinct tissue microenvironments and ligand repertoires.

SUMMARY OF KEY CONTENTS: This review provides a comprehensive synthesis of TREM2 immunobiology, detailing how ligand engagement-including cell-surface phospholipids and apolipoprotein E (ApoE)-activates the DAP12/DAP10-SYK-PI3K-mTOR signalling axis. This coordinated intracellular cascade instructively drives myeloid adaptation towards metabolically competent disease-associated microglia (DAM) and lipid-associated macrophage (LAM) states, sustaining bioenergetics and debris clearance under pathological stress. Across neurodegenerative proteinopathies and acute cerebral ischemia, TREM2 signalling is predominantly neuroprotective by promoting aggregate compaction and mitigating secondary excitotoxicity, although chronic dysregulated activation may drive stage-dependent neuroinflammation. In peripheral inflammatory pathologies such as rheumatoid arthritis and sepsis, TREM2 fine-tunes macrophage efferocytosis and systemic metabolic thresholds. In oncology, TREM2 displays a complex, microenvironment-dependent divergence: in central nervous system malignancies such as glioblastoma (GBM), TREM2 exerts controversial, stage-dependent effects, spanning microglial tumour containment in early stages versus pro-tumoural myelin recycling and immunosuppression by monocyte-derived macrophages in post-treatment recurrence; conversely, in peripheral solid tumours, monocyte-derived TREM2+ tumour-associated macrophages (TAMs) predominantly orchestrate an immunosuppressive, nutrient-deprived niche that impairs cytotoxic T-cell function. Furthermore, we synthesise emerging paradigms along the bidirectional microbiome-gut-brain-tumour axis, elucidating how commensal and intra-tumoural microbial cues dynamically calibrate myeloid signalling tone and therapeutic susceptibility.

CONCLUSION: We address translation bottlenecks-including blood-brain barrier (BBB) shuttles, human trial scarcity and soluble TREM2 (sTREM2) biomarker harmonisation-outlining a biomarker-guided, context-tailored precision therapeutic framework for targeting the TREM2 axis.},
}

Humans
*Receptors, Immunologic/metabolism
*Membrane Glycoproteins/metabolism
*Signal Transduction
*Myeloid Cells/metabolism/immunology
*Neoplasms/therapy/immunology
Animals
*Immunotherapy/methods
*Neurodegenerative Diseases/therapy/immunology

@article {pmid42865340,
year = {2026},
author = {Kamonnat, C and Thongdechsri, S and Kraokaew, P and Niamnont, N and Sobhon, P and Meemon, K},
title = {Protective Role of Holothuria leucospilota Extract Against Amyloid-β Toxicity via Autophagy and Antioxidant Mechanisms in Caenorhabditis elegans Model.},
journal = {Oxidative medicine and cellular longevity},
volume = {2026},
number = {1},
pages = {e1471919},
pmid = {42865340},
issn = {1942-0994},
support = {//National Research Council of Thailand/ ; N42A660511//Mahidol University/ ; AN-KME-3-66-02//Central Instrument Facility (CIF)/ ; },
mesh = {Animals ; *Caenorhabditis elegans/drug effects/metabolism ; *Amyloid beta-Peptides/toxicity/metabolism ; *Autophagy/drug effects ; *Antioxidants/pharmacology ; *Holothuria/chemistry ; Oxidative Stress/drug effects ; Disease Models, Animal ; Reactive Oxygen Species/metabolism ; *Plant Extracts/pharmacology ; Caenorhabditis elegans Proteins/metabolism ; Alzheimer Disease/drug therapy ; Animals, Genetically Modified ; },
abstract = {Alzheimer's disease (AD) is a major global health challenge characterized by cognitive decline and neuronal degeneration driven by amyloid-β (Aβ) aggregation and oxidative stress. Given the limited efficacy and adverse effects of current pharmacological therapies, food-derived bioactive compounds have gained increasing attention as potential preventive strategies against neurodegenerative disorders. In this study, we investigated the neuroprotective effects of Holothuria leucospilota extracts using a transgenic Caenorhabditis elegans model of AD. Our results demonstrated that H. leucospilota hexane extract (HLHE) at 500 µg/mL significantly delayed Aβ-induced paralysis and improved chemotaxis behavior. Consistently, HLHE treatment reduced Aβ deposition and decreased both high- and low-molecular weights of Aβ oligomers, as determined by automated Western blot analysis. Additionally, HLHE also reduced reactive oxygen species (ROS) levels. Transcriptomic and RT-qPCR analyses revealed that HLHE enhanced autophagic activity through the upregulation of bec-1 (autophagy initiation) and lysosomal genes (cpr-1, cpr-2, and cpr-5). Furthermore, HLHE activated antioxidant defense pathways via the insulin/IGF-1 signaling (IIS) axis, specifically upregulating genes associated with SKN-1 pathway (pmk-1, skn-1, gst-4, and gst-10) and HSF-1 pathway (hsf-1, hsp-16.1, hsp-12.6, and mtl-1). HLHE also promoted nuclear localization of SKN-1 and increased expression of its downstream target gst-4. Chemical analysis revealed that HLHE contained arachidonic acid (21.12%) and other bioactive lipid compounds as major constituents, suggesting a synergistic role in promoting autophagy and antioxidant responses. Collectively, this study suggests that HLHE confers neuroprotection against Aβ-induced toxicity by activating autophagy and oxidative stress defense mechanisms, supporting its potential development as a food-derived preventive or therapeutic agent for AD.},
}

Animals
*Caenorhabditis elegans/drug effects/metabolism
*Amyloid beta-Peptides/toxicity/metabolism
*Autophagy/drug effects
*Antioxidants/pharmacology
*Holothuria/chemistry
Oxidative Stress/drug effects
Disease Models, Animal
Reactive Oxygen Species/metabolism
*Plant Extracts/pharmacology
Caenorhabditis elegans Proteins/metabolism
Alzheimer Disease/drug therapy
Animals, Genetically Modified

@article {pmid42865480,
year = {2026},
author = {Li, SY and Zhang, JX and Huang, LZ and Wu, HB and Ye, YB and Liu, A and Chen, J and Lai, S},
title = {Efficacy and safety of lecanemab monoclonal antibody in the treatment of mild to moderate Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1947129},
pmid = {42865480},
issn = {1663-9812},
abstract = {BACKGROUND: Lecanemab is a novel therapy for Alzheimer's disease (AD), but comprehensive evidence is lacking. This systematic review and meta-analysis evaluated the efficacy and safety in AD.

METHODS: Registered in PROSPERO (CRD420251146867). PubMed, Embase, Cochrane Library, Web of Science, and Scopus were searched for English-language RCTs. Efficacy and safety were evaluated using the risk difference with a Mantel-Haenszel fixed-effects model. Study quality and sensitivity were assessed using Cochrane risk-of-bias and leave-one-out methods. Primary outcomes: mean changes in Alzheimer's Disease Composite Score (ADCOMS), Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and amyloid burden on positron emission tomography (PET). Secondary: adverse events including amyloid-related imaging abnormalities with edema (ARIA-E), ARIA with hemorrhage (ARIA-H), death, treatment-emergent adverse events (TEAEs), headache, dizziness, and urinary tract infection.

RESULTS: A total of five articles involving 8 clinical trials were included. Based on the fixed-effect model, lecanemab treatment significantly improved cognitive performance on ADCOMS (SMD -0.1999, 95% CI [-0.2831, -0.1167], I[2] = 0%, P < 0.00001), CDR-SB (SMD -0.1853, 95% CI [-0.2683, -0.1024], I[2] = 0%, P < 0.0001), ADAS-Cog (SMD -0.1821, 95% CI [-0.2670, -0.0973], I[2] = 0%, P < 0.0001) and amyloid burden on PET (SMD -1.1872, 95% CI [-2.2474, -0.1270], I[2] = 96%, P = 0.03). Sensitivity analysis indicated stability. However, lecanemab was associated with an increased risk of TEAEs (MH RR 1.0730, 95% Cl [1.0296, 1.1183], I[2] = 0%, P = 0.0008) and an increased risk of headache (MH RR 1.3617, 95% Cl [1.0243, 1.8103], I[2] = 0%, P = 0.03). Sensitivity analysis indicated that both results were stable. The lecanemab group showed no significant differences in the risks of death, dizziness, or urinary tract infection compared with the control group. In addition, the lecanemab group showed a significantly increased risk of ARIA-E (MH RR 5.9948, 95% CI [3.9047, 9.2037], I[2] = 86%, P < 0.00001) and ARIA-H (MH RR 1.7490, 95% CI [1.3896, 2.2014], I[2] = 41%, P < 0.00001). Sensitivity analyses confirmed the stability of the TEAE finding, while the headache result should be interpreted with caution due to the limited number of studies. After excluding Honig et al. (OLE) 2021 via leave-one-out, results became stable, likely due to its open-label design.

CONCLUSION: Lecanemab slowed cognitive decline versus placebo in mild-to-moderate AD by ADCOMS, CDR-SB, and ADAS-Cog. High heterogeneity in PET amyloid burden warrants future RCTs. Nevertheless, lecanemab was associated with an increased risk of TEAEs and headache.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251146867.},
}

@article {pmid42865621,
year = {2026},
author = {Tan, W and Han, X and Wang, X and Tang, M and Li, S and Liu, H and Zhang, J and Wang, J and Liu, G},
title = {Multimodal MRI to elucidate cross-organ coupling mechanisms of the heart-brain axis.},
journal = {Frontiers in cardiovascular medicine},
volume = {13},
number = {},
pages = {1914265},
pmid = {42865621},
issn = {2297-055X},
abstract = {Cardiovascular and cerebrovascular diseases (CCVDs) are leading causes of mortality and disability worldwide, and their development is closely linked to bidirectional interactions between the heart and the brain. The heart-brain axis, a systemic framework that integrates neural, humoral, and inflammatory pathways, provides an important theoretical basis for understanding heart-brain comorbidities. With continuous advances in magnetic resonance imaging(MRI), research in this field has progressively shifted from the traditional single-organ diagnostic model to cross-organ and system-oriented strategies for prevention and management. Centered on cardiac magnetic resonance (CMR) and brain MRI, and complemented by quantitative, diffusion, functional, ultra-high-field, and metabolic imaging techniques, multimodal MRI has become a powerful tool for comprehensively characterizing myocardial remodeling, alterations in brain networks, and their coupling relationships. These techniques have been widely applied in studies of representative heart-brain comorbidities, including cardiac dysfunction associated with acute brain injury, cognitive impairment related to heart failure, and cardiovascular abnormalities associated with neurodegenerative diseases, such as Alzheimer's disease (AD). Such studies have not only revealed structural and functional alterations in the heart and brain but have also provided important insights into potential mechanisms, including autonomic imbalance, neuroendocrine activation, and inflammatory responses. However, current heart-brain axis research remains largely based on correlational analyses, whereas causal inference and characterization of dynamic mechanisms remain insufficient. In addition, significant challenges persist in multimodal data integration and clinical translation. Overall, MRI is driving heart-brain axis research from structural characterization toward mechanistic investigation. In the future, integrating imaging, physiological, and genetic information may enable early identification, risk stratification, and precision intervention for heart-brain comorbidities, thereby promoting a transition in medical practice from single-organ management to systemic prevention and treatment.},
}

@article {pmid42865677,
year = {2026},
author = {Wahbeh, H and Cooley, S and Chamberlin, SR and Brophy, T and Hameroff, S},
title = {Home-administered unfocused transcranial ultrasound in subjective cognitive decline and dementia: an open-label, uncontrolled feasibility pilot study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1937897},
pmid = {42865677},
issn = {1663-4365},
abstract = {BACKGROUND: Memory and cognitive impairments remain disabling, with few effective treatments. Low-intensity transcranial ultrasound (TUS) is a non-invasive neuromodulation approach with a favorable safety profile and preliminary evidence of cognitive benefit, with one hypothesized but unproven mechanism involving microtubule resonance and reassembly.

OBJECTIVES: This open-label pilot study evaluated the safety and preliminary efficacy of the US Pro2000 unfocused ultrasound device in adults with memory or cognitive difficulties, a sample spanning subjective cognitive decline among self-administering participants to diagnosed dementia among caregiver-rated recipients, and described self-reported symptom trajectories.

METHODS: In a within-participant design, adults with self-reported cognitive impairment, or their caregivers, applied the device at the right temporal window for 5 min three times daily (target 15 min/day), in cycles of 3 weeks on and 1 week off. Outcomes (GAD-7, CESD-5, Inoue battery, and caregiver-rated MDS 3.0) and adverse events were collected online. Mixed-effects models with age and device-use covariates assessed change over time, with False Discovery Rate correction within aim.

RESULTS: Twenty-seven participants enrolled and 26 initiated treatment. Across 2,174 daily assessments, no serious or unanticipated adverse events occurred; only headache (15.4%) and transient jaw clenching (3.8%) were possibly related, and none caused discontinuation. Among self-administered participants, depression (CESD-5) declined significantly (p_FDR = 0.016) and five of eight monthly self-report symptoms improved, including memory, word-finding, and problem-solving (all p_FDR ≤ 0.040); anxiety trended downward, and the objective cognitive battery, near ceiling at baseline, did not change. Caregiver-rated outcomes were stable. Device use showed no dose response, and sensitivity analyses were consistent.

CONCLUSION: Home-based self-administered low-intensity TUS was well tolerated, with only mild transient events, although adverse-event ascertainment relied on unblinded self-report and relatedness judgments were made by unblinded investigators. Efficacy signals were confined to self-report, while objective cognition and caregiver ratings were unchanged. The uncontrolled design, small subgroups, and reliance on self-report preclude causal inference. These findings support the safety and feasibility of TUS and justify an adequately powered, double-blind, sham-controlled trial.},
}

@article {pmid42865929,
year = {2026},
author = {Ponomareva, EV and Selezneva, ND and Boksha, IS and Savushkina, OK and Prokhorova, TA and Tereshkina, EB and Zozulya, SA and Gavrilova, SI and Kolykhalov, IV},
title = {Pilot clinical study of Taxifolin Aqua effect in patients with amnestic mild cognitive impairment.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1814042},
pmid = {42865929},
issn = {1664-0640},
abstract = {Taxifolin (dihydroquercetin), a potent antioxidant flavonoid, shows promise for neurodegenerative conditions. Our pilot study aimed at evaluation the efficacy and safety of Taxifolin in patients with amnestic mild cognitive impairment (aMCI) and monitored a set of blood measures. Twenty-three patients (18 female; aged 53-87) received dihydroquercetin oral solution for 8 weeks with a 4-week follow-up period in an open-label study design. Thirteen patients with aMCI were monitored as controls. Outcomes were assessed using cognitive status (MMSE, MoCA, FCSRT-IR), neuropsychiatric symptoms' (NPI-Q, HDRS), and rater's impression (CGI) scales, along with blood measures monitoring (glutathione reductase (GR), glutamate dehydrogenase (GDH), and superoxide dismutase (SOD); plasma neutrophil elastase (NE), alpha-1-proteinase inhibitor (alpha-1PI)). Responder classification using composite Z-score changes was based on all clinical scales. Results: Eleven patients were classified as responders, showing significant MMSE and MoCA improvement (mean +2.73 points, p=0.001) sustained through 4-week follow-up. Non-responders and control group showed slight cognitive decline. Composite Z-score changes at the 4-week follow-up revealed differences between responders/non-responders (ANOVA F(2,20)=17.38, p=0.001); biomarker analysis revealed difference in NE/alpha-1PI ratio (p=0.034), SOD (p=0.023), and GR dynamics (p=0.022), which correlated negatively with clinical response (R=-0.547, p=0.007), and baseline GDH (p=0.049). Conclusion: Taxifolin treatment resulted in significant cognitive benefits in ~half of aMCI patients, with effects sustained for one month post-treatment. Biomarker changes reveal possible mechanisms involving oxidative stress modulation and inflammatory pathways. These findings support further controlled trials of Taxifolin in populations at risk of Alzheimer's disease.},
}

@article {pmid42866370,
year = {2026},
author = {Wang, T and Wang, L and Cao, J and Zhao, Y and He, Z and Lu, F},
title = {Remodeling of the brain immune microenvironment in Alzheimer's disease: interactions among microglia, astrocytes, complement, and the neurovascular unit.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1956600},
pmid = {42866370},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/immunology/pathology/metabolism ; *Microglia/immunology/metabolism/pathology ; *Astrocytes/immunology/metabolism/pathology ; *Complement System Proteins/immunology/metabolism ; *Brain/immunology/pathology/metabolism/blood supply ; Animals ; *Cellular Microenvironment/immunology ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease is defined by amyloid-β deposition and tau pathology, yet comparable pathological burdens do not necessarily correspond to similar cognitive trajectories, regional patterns of injury, or treatment responses. This discordance suggests that the cellular and tissue microenvironment may materially shape disease progression. Genetic studies, single-cell and spatial omics, and human-derived models further indicate that microglia, astrocytes, the complement system, and the neurovascular unit undergo coordinated remodeling during the preclinical phase of AD and influence pathological spread, synaptic injury, and neurodegeneration through intercellular interactions. Remodeling of the brain immune microenvironment is regionally specific, stage dependent, and heterogeneous across cellular states; conventional pro-inflammatory/anti-inflammatory or activated/resting dichotomies therefore fail to capture its dynamics. This review examines the remodeling of the AD brain immune microenvironment through interactions among microglia, astrocytes, complement, and the neurovascular unit, with emphasis on their roles in Aβ and tau pathology, synaptic injury, lipid homeostasis, and vascular dysfunction, and considers the interpretive limits of single-cell and spatial-omics evidence. Current evidence supports a dynamically reconfigured system rather than a uniformly escalating inflammatory response. Therapeutic strategies should move beyond broad anti-inflammatory approaches to preserve effective pathological clearance within appropriate disease windows, limit maladaptive synaptic injury, and restore glial and neurovascular homeostasis.},
}

Humans
*Alzheimer Disease/immunology/pathology/metabolism
*Microglia/immunology/metabolism/pathology
*Astrocytes/immunology/metabolism/pathology
*Complement System Proteins/immunology/metabolism
*Brain/immunology/pathology/metabolism/blood supply
Animals
*Cellular Microenvironment/immunology
Amyloid beta-Peptides/metabolism

@article {pmid42866775,
year = {2026},
author = {Bhatia, V and Khatak, A},
title = {A positive Alzheimer's blood biomarker is not a diagnosis: the presence-primacy-permission framework for plasma p-tau217.},
journal = {Annals of medicine and surgery (2012)},
volume = {88},
number = {10},
pages = {6232-6234},
pmid = {42866775},
issn = {2049-0801},
abstract = {Validated plasma phosphorylated tau 217 (p-tau217) assays identify Alzheimer disease pathology with high accuracy. Wider clinical use creates a risk of postanalytic misclassification when pathology is converted directly into a clinical diagnosis or treatment decision. This editorial examines why accuracy relative to amyloid positron emission tomography or cerebrospinal fluid biomarkers does not establish that Alzheimer disease is the principal cause of a patient's cognitive syndrome. It describes three substitutions: pathology for diagnosis, presence for primacy, and diagnosis for treatment eligibility. We propose the presence-primacy-permission framework to distinguish confirmation of pathology from clinical-biological concordance and treatment suitability. Presence requires appropriate patient selection, a validated assay, and context-specific interpretation. Primacy requires integration of cognitive phenotype, trajectory, functional status, neurologic examination, structural imaging, and coexisting pathology. Permission requires assessment of clinical stage, hemorrhagic risk, treatment feasibility, and patient goals. Separate documentation of the biomarker result, syndrome, etiologic attribution, and actionability may reduce premature diagnostic closure while preserving the clinical value of p-tau217.},
}

@article {pmid42867612,
year = {2026},
author = {Fang, X and Border, JJ and Zhang, H and Morgan, GC and Gregory, A and Hanscom-Trofy, Y and Dong, R and Yang, J and Hwang, SH and Morisseau, C and Hammock, BD and Fan, F and Roman, RJ},
title = {Inhibition of soluble epoxide hydrolase rescues cognitive deficits by preserving neurovascular integrity and attenuating glial and neuropathology in diabetic-related dementia.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42867612},
issn = {2509-2723},
support = {AG079336//NIH/ ; AG057842/AG/NIA NIH HHS/United States ; AG094068/AG/NIA NIH HHS/United States ; R35ES030443/ES/NIEHS NIH HHS/United States ; U54NS127758/NS/NINDS NIH HHS/United States ; A25-1690//Harrington Discovery Institute, University Hospitals/ ; 25PRE1365157//American Heart Association/ ; 25POST1363814//American Heart Association/ ; TRIBA/ Physiology Faculty Startup Fund//Augusta University/ ; },
abstract = {Diabetes mellitus (DM) is a major risk factor contributing to the development of Alzheimer's disease-related dementias (ADRD). While one of the early symptoms of both Alzheimer's disease (AD) and DM-related ADRD is a reduction in cerebral blood flow, the underlying biological mechanisms driving this decline remain to be fully elucidated. Genome-wide association studies have linked AD/ADRD to single-nucleotide polymorphisms in the gene encoding soluble epoxide hydrolase (sEH), an enzyme we previously reported to be upregulated in the brains of an AD rat model. Our previous studies also demonstrated that chronic sEH inhibition with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) preserves hippocampal-dependent spatial learning and memory and improves cerebral hemodynamics in both AD and DM-ADRD models. In the present study, we found that chronic TPPU treatment (1 mg/kg/day) reduced sEH expression in the brain, improved cortical-based non-spatial recognition memory involving both cortical and hippocampal networks, and reduced anxiety in DM-ADRD rats. TPPU improved brain perfusion and normalized impaired whisker-evoked functional hyperemia, an effect associated with increased Kir2.1 expression and neurovascular coupling in cerebral capillaries. Furthermore, TPPU increased tight junction protein expression (ZO-1 and OCLN), mitigated capillary rarefaction, and suppressed astrocyte and microglial activation in DM-ADRD rats. At the cellular level, TPPU attenuated hippocampal neurodegeneration, restored the expression of synaptic proteins (PSD95 and SY38), and reduced levels of proinflammatory chemokines, including MCP-1, RANTES, and MIP-1α, in the hippocampus of DM-ADRD rats. In conclusion, TPPU preserves cognitive function in DM-ADRD by mitigating cerebrovascular dysfunction, neuroinflammation and gliosis, thereby preserving synaptic integrity and neuronal survival, and represents a promising therapeutic strategy for DM-ADRD.},
}

@article {pmid42868046,
year = {2026},
author = {Lv, C and Luo, Q and Jin, F and Shao, Q and Qiu, Y and Ni, J and Liu, J and Qing, H and Quan, Z},
title = {Intermittent hypoxia training alleviates cerebral hypoperfusion and amyloid-β deposition in a mixed dementia model established by bilateral common carotid artery stenosis in early-stage 5xFAD mice.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261497235},
doi = {10.1177/13872877261497235},
pmid = {42868046},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is the most common form of dementia and often coexists with vascular pathology in clinical settings, resulting in mixed dementia with more severe symptoms and more rapid progression.ObjectiveTo investigate whether chronic cerebral hypoperfusion aggravates early AD-related pathology, we established a mixed dementia-like model by inducing bilateral common carotid artery stenosis (BCAS) in early-stage 5xFAD mice and evaluated the effects of intermittent hypoxia treatment (IHT).MethodsEarly-stage 5xFAD mice were subjected to BCAS to induce chronic cerebral hypoperfusion. Cognitive performance, cerebral perfusion, amyloid-β (Aβ) deposition, glial reactivity, tight-junction transcripts, and perivascular astrocyte-vascular organization were assessed. The therapeutic effects of IHT were then evaluated in this mixed dementia-like model.ResultsBCAS-induced hypoperfusion aggravated cognitive impairment in early-stage 5xFAD mice and accelerated pathological changes, including increased Aβ burden and stronger glial reactivity. These changes were accompanied by altered tight-junction transcripts and impaired perivascular astrocyte-vascular organization. IHT mitigated several features of the mixed dementia phenotype, including cerebral hypoperfusion, Aβ accumulation, glial reactivity, and altered perivascular AQP4/CD31 organization, while partially improving cognitive performance.ConclusionsChronic cerebral hypoperfusion can exacerbate early AD-related pathological and cognitive changes. IHT may alleviate mixed dementia-like phenotypes by improving cerebral perfusion, with accompanying changes in perivascular AQP4/CD31 organization and tight-junction transcripts.},
}

@article {pmid42869342,
year = {2026},
author = {Mikalauskaite, K and Veiveris, D and Smirnovas, V and Ziaunys, M},
title = {Effect of freeze-thaw cycle induced oligomers on alpha-synuclein liquid-liquid phase separation and aggregation.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {154845},
doi = {10.1016/j.ijbiomac.2026.154845},
pmid = {42869342},
issn = {1879-0003},
abstract = {Protein aggregation in the form of amyloid fibrils is linked with the onset and progression of several widespread and incurable disorders, including neurodegenerative Alzheimer's and Parkinson's diseases. Despite decades of research and countless attempts to discover potential aggregation-altering treatment modalities, there are still no effective cures for the majority of amyloid-related disorders. This is, in part, due to our incomplete understanding of the underlying factors that influence the phase separation and aggregation of these various disease-related proteins. Over the last few years, it has been shown that even factors such as storage conditions or sample preincubation times can affect the formation kinetics of amyloid fibrils. In the case of alpha-synuclein, even the protein purification procedure yielded different concentrations of oligomeric species, which altered the aggregation mechanism. In this work, we further explore the role of alpha-synuclein oligomers by inducing their formation via freeze-thaw cycles and analyzing their effect on liquid-liquid and liquid-solid phase transitions. Using real-time kinetic monitoring, brightfield microscopy, Fourier-transform infrared spectroscopy and atomic force microscopy, we show that the presence of freeze-thaw cycle induced alpha-synuclein oligomers has significant effects on its condensate assembly and subsequent aggregation, as well as the final structure of the formed aggregates.},
}

@article {pmid42869847,
year = {2026},
author = {Liu, X and de Boer, SCM and Tartaglia, MC and , },
title = {Sex-specific brain reserve and progression from mild cognitive impairment to Alzheimer's disease dementia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71913},
doi = {10.1002/alz.71913},
pmid = {42869847},
issn = {1552-5279},
support = {//Donald Weaver Postdoctoral Fellowship/ ; //Early Career Grant of Alzheimer Nederland/ ; //Brain Canada-Krembil/ ; //Canadian Institute of Health Research/ ; //Tanenbaum Institute of Research in Sports Science/ ; //Weston Family Foundation/ ; //Michael J. Fox Foundation for Parkinson's Research/ ; },
mesh = {Humans ; Female ; *Alzheimer Disease/pathology/diagnostic imaging/cerebrospinal fluid ; *Cognitive Dysfunction/pathology/diagnostic imaging/cerebrospinal fluid ; Male ; Disease Progression ; *Brain/pathology/diagnostic imaging ; tau Proteins/metabolism ; Aged ; Positron-Emission Tomography ; *Sex Characteristics ; Magnetic Resonance Imaging ; Atrophy ; Longitudinal Studies ; Aged, 80 and over ; Gray Matter/pathology/diagnostic imaging ; Biomarkers/cerebrospinal fluid ; },
abstract = {INTRODUCTION: Sex differences exist in Alzheimer's disease (AD) treatment response, but the role of sex in disease development and progression remains unclear.

METHODS: We performed multimodal analyses of AD biomarker-positive individuals with mild cognitive impairment (MCI) and AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI; MCI n = 593, AD n = 270) and National Alzheimer's Coordinating Center (MCI n = 436, AD n = 174). Baseline gray matter volume (GMV) was compared by sex. In ADNI, tau positron emission tomography burden and cerebrospinal fluid growth-associated protein 43 (GAP-43) were assessed. Longitudinal analyses examined atrophy and conversion from MCI to dementia.

RESULTS: Females with MCI exhibited greater baseline GMV than males primarily in the thalamus, caudate, cerebellum, postcentral gyrus, and middle cingulate gyrus, with no differences at the AD stage. Despite this, females exhibited higher baseline GAP-43, greater tau burden in temporal and parietal regions, and more rapid annual hippocampal atrophy. Conversion rates were similar.

DISCUSSION: Findings suggest that females may tolerate greater pathology at early stages but experience faster neurodegeneration later, supporting sex-specific disease trajectories and highlighting the need for sex-informed biomarkers.},
}

Humans
Female
*Alzheimer Disease/pathology/diagnostic imaging/cerebrospinal fluid
*Cognitive Dysfunction/pathology/diagnostic imaging/cerebrospinal fluid
Male
Disease Progression
*Brain/pathology/diagnostic imaging
tau Proteins/metabolism
Aged
Positron-Emission Tomography
*Sex Characteristics
Magnetic Resonance Imaging
Atrophy
Longitudinal Studies
Aged, 80 and over
Gray Matter/pathology/diagnostic imaging
Biomarkers/cerebrospinal fluid

@article {pmid42858079,
year = {2026},
author = {Yang, X and Ye, T and He, Y and Zhao, J and Wang, J and Cheng, X},
title = {Qi-Fu-Yin Attenuates Frailty by Regulating Gut Microbiota and Neuroendocrine Hormones in 5xFamilial Alzheimer's Disease Transgenic Mice.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {236},
pages = {},
doi = {10.3791/73003},
pmid = {42858079},
issn = {1940-087X},
mesh = {Animals ; *Alzheimer Disease/drug therapy/microbiology/blood/metabolism ; Mice, Transgenic ; Mice ; *Gastrointestinal Microbiome/drug effects ; *Drugs, Chinese Herbal/pharmacology/administration & dosage ; *Frailty/drug therapy/microbiology ; Female ; Male ; Disease Models, Animal ; },
abstract = {Frailty is a common and debilitating feature of Alzheimer's disease (AD), yet effective therapeutic strategies targeting both cognitive decline and physical frailty remain limited. Qi-Fu-Yin (QFY), a traditional Chinese herbal formulation, has been used to treat aging-related disorders, but its effects on frailty in AD and the underlying mechanisms are unclear. This study aimed to evaluate whether QFY alleviates frailty in 5xFamilial Alzheimer's Disease (FAD) transgenic mice and to explore the potential involvement of gut microbiota and neuroendocrine hormones. Mice were treated with QFY at low (2.8 g/kg), medium (5.6 g/kg), or high (11.2 g/kg) doses, or with donepezil as a positive control, for 194 days. Frailty-related behaviors were assessed using CatWalk gait analysis, grip strength, rotarod, nest-building, and aging scoring. Plasma hormone levels were measured, and fecal gut microbiota composition and function were analyzed by 16S rRNA sequencing and metagenomic analysis. QFY treatment significantly improved gait parameters, grip strength, motor coordination, nesting ability, and reduced aging scores in 5xFAD mice, with effects comparable to or superior to those of donepezil. QFY also restored aberrant levels of estradiol, testosterone, and corticosterone, and reshaped gut microbiota composition, particularly by increasing the abundance of Adlercreutzia, which negatively correlated with senescence and testosterone levels. Functional metagenomics revealed that QFY partially restored disease-associated microbial pathways, including those involved in carbohydrate metabolism and virulence. These findings suggest that QFY alleviates frailty in 5xFAD mice, with effects associated with concurrent modulation of gut microbiota and neuroendocrine function, though causal relationships require further validation. These findings support further investigation of QFY as a potential intervention for AD-associated frailty.},
}

Animals
*Alzheimer Disease/drug therapy/microbiology/blood/metabolism
Mice, Transgenic
Mice
*Gastrointestinal Microbiome/drug effects
*Drugs, Chinese Herbal/pharmacology/administration & dosage
*Frailty/drug therapy/microbiology
Female
Male
Disease Models, Animal

@article {pmid42858322,
year = {2026},
author = {Yang, Y and Zhang, X and Zan, X and Niu, C and Wei, X and Feng, P and Li, G and Gao, M},
title = {A Clearance-Repair-Activation Framework for Alzheimer's Disease: A Perspective and Validation Roadmap.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.1040},
pmid = {42858322},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) is a heterogeneous clinicobiological syndrome involving impaired protein clearance, neuroinflammation, synaptic and cellular injury, network dysfunction, and progressive functional decline. Amyloid-directed antibodies provide an evidence-based treatment backbone for selected patients with early symptomatic AD, but adjunctive strategies may be needed to address other disease mechanisms. This Perspective proposes a clearance-repair-activation framework for hypothesis-driven research. Clearance includes established pharmacological treatment and risk management as well as investigational drainage approaches; lymphaticovenous anastomosis (LVA) and deep cervical lymphaticovenous anastomosis (dcLVA) are considered only as research options within this broader domain. Repair includes neural stem-cell (NSC), induced pluripotent stem-cell-derived, engineered-cell, and secretome-based strategies, for which AD evidence remains predominantly preclinical. Activation encompasses invasive and non-invasive stimulation, sensory entrainment, neurofeedback, brain-computer interface (BCI) monitoring, and cognitive rehabilitation; BCI is positioned mainly as an experimental monitoring and adaptive rehabilitation platform. We define falsifiable links between clearance and repair readiness and between repair markers and activation responsiveness, consider adaptive and parallel alternatives to fixed sequencing, and integrate disease stage, heterogeneity, regulation, and combination-trial design. Informatics is limited to trial infrastructure and safety governance. The validation roadmap specifies success criteria, stop rules, interaction testing, clinically meaningful outcomes, and long-term surveillance.},
}

@article {pmid42858330,
year = {2026},
author = {Zhang, K and Zhang, Y and Jiang, X and Chen, X},
title = {Neuroimmune State Configurations at the Amyloid-Tau Interface in Alzheimer's Disease: A Testable Framework.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0888},
pmid = {42858330},
issn = {2152-5250},
abstract = {Neuroimmune mechanisms are central to Alzheimer's disease (AD), but a single continuum of "more inflammation" does not explain why similar amyloid-β (Aβ) and tau burdens are associated with different clinical trajectories, tissue responses, and treatment risks. We present a testable neuroimmune-state framework that integrates, rather than replaces, the AT(N) system, cellular-phase models, and transcriptional descriptions of disease-associated microglia and reactive astrocytes. The framework treats neuroimmune states as multidimensional, regionally heterogeneous configurations defined by pathological substrate, cellular program, biological target, vascular and aging context, and measurable patient-level readouts. We distinguish four meanings of the amyloid-tau interface: a biomarker interface, a spatial tissue interface, a cellular-state interface, and a clinical-progression interface. We then examine the hypothesis of phagocytic target switching, in which clearance pathways that support plaque compaction or debris removal may, under selected tau- and complement-rich conditions, contribute to removal of stressed but potentially functional synapses. We explicitly separate evidence from longitudinal human studies, cross-sectional biomarkers, human genetics, postmortem tissue, animal models, and in vitro systems. Current biomarkers cannot yet assign patients to validated discrete neuroimmune states; proposed state readers should therefore be probabilistic, allow regional coexistence and parallel vascular-immune trajectories, and be tested for incremental value beyond established AD biomarkers and co-pathologies. Finally, we organize immune-directed interventions by clinical evidence level and frame stage matching as a research strategy rather than a treatment algorithm. The model is useful only if its predictions can be prospectively supported or falsified.},
}

@article {pmid42858944,
year = {2026},
author = {Patel, DR and Rangasamy, SB and Gorai, S and Paidi, RK and Pahan, K},
title = {Glyceryl tribenzoate, a flavoring agent, stimulates hippocampal plasticity and protects memory via PPARα.},
journal = {Neurochemistry international},
volume = {201},
number = {},
pages = {106270},
doi = {10.1016/j.neuint.2026.106270},
pmid = {42858944},
issn = {1872-9754},
abstract = {Glyceryl tribenzoate (GTB) or tribenzoin is a flavoring agent with characteristic anti-microbial property. We have already delineated GTB's immunomodulatory role via the enrichment of regulatory T cells in mouse models of multiple sclerosis and anti-neuroinflammatory role via the reduction of glial activation in a monkey model of Parkinson's disease and a mouse model of Huntington's disease. However, its role has never been explored in Alzheimer's disease (AD), the most common neurodegenerative disorder in human. This study underlines the importance of GTB in promoting the growth and function of hippocampal neurons via upregulation of plasticity-associated genes, enrichment of dendritic spines and stimulation of inotropic calcium influx. Accordingly, oral GTB improved hippocampal plasticity and protected memory and learning in 5xFAD mice. Similarly, GTB treatment also reduced cerebral plaque load and increased the life span of aged 5xFAD mice. Interestingly, we observed that peroxisome proliferator-activated receptor alpha (PPARα), a nuclear hormone receptor, served as a receptor of GTB. Consequently, GTB was shown to improve hippocampal plasticity and increase cognitive functions in 5xFAD, but not 5xFAD/Ppara-null, mice, indicating an important role of PPARα in GTB-mediated neuroprotection. These results suggest that oral GTB may have therapeutic importance for improving hippocampal functions in AD patients.},
}

@article {pmid42859348,
year = {2026},
author = {Lin, W and Shu, Z and Liu, G and Fang, J and Ding, S},
title = {The Gut-Brain Axis and Neurodegenerative Diseases: From Mechanistic Pathways to Therapeutic Interventions.},
journal = {Probiotics and antimicrobial proteins},
volume = {},
number = {},
pages = {},
pmid = {42859348},
issn = {1867-1314},
support = {2024RC2053//Yuelushan Laboratory joint talent introduction project/ ; Grant No. kq2502176//Natural Science Foundation of Changsha, China/ ; 24B0219//Scientific Research Project of Hunan Provincial Department of Education/ ; 2025JGZD053//Hunan Province Postgraduate Education Teaching Reform Research Project/ ; 2023YFD1301200//National Key Research and Development Program of China/ ; HARS-06//Hunan Poultry Industry Technology System/ ; },
abstract = {As the global population ages, the incidence of neurodegenerative diseases (NDDs) has increased. Neurodegenerative diseases have complex pathogenesis and currently lack fundamental treatment methods. The gut-brain axis (GBA) participates in the pathogenesis of NDDs through bidirectional communication between the gut microbiota and the central nervous system (CNS). This review systematically introduces the pathogenic characteristics of representative NDDs such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), as well as the association mechanisms between these diseases and GBA. The pathogenic characteristics of NDDs are closely related to changes in the composition of the gut microbiota and differences in gut microbiota metabolites (such as short-chain fatty acids (SCFAs), neurotransmitters, tryptophan metabolites, etc.). These changes influence the CNS through multiple pathways, including neuroendocrine, vagus nerve, and immune regulation, ultimately contributing to the onset and progression of the diseases. Furthermore, we have collected and summarized preclinical and clinical evidence from recent years regarding therapeutic interventions based on the GBA mechanism, including probiotics, prebiotics, and fecal microbiota transplantation (FMT). Nevertheless, major knowledge gaps remain, particularly regarding causality between gut microbiota changes and NDDs, the underlying molecular mechanisms, and the clinical efficacy of GBA-targeted therapies. This article aims to review the mechanisms of the interaction between the gut microbiota and the brain in neurodegenerative diseases, and based on the existing experimental evidence, provide theoretical basis and future development directions for future prevention and treatment strategies targeting GBA.},
}

@article {pmid42860159,
year = {2026},
author = {Wang, M and Zhao, H and Lin, X and Ye, Z and Tu, B and Yang, Y and Wang, C and Fang, X and Fang, Q},
title = {Field-assisted interfacial passivation: Microwave-enhanced EGCG remodeling of amyloid-β42 aggregates.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {154811},
doi = {10.1016/j.ijbiomac.2026.154811},
pmid = {42860159},
issn = {1879-0003},
abstract = {Amyloid misfolding and self-assembly are central pathological events of Alzheimer's disease and related proteinopathies. Although soluble oligomers are widely considered as the primary toxic species, how therapeutic modulators alter toxicity-relevant aggregate surfaces remains poorly understood. Here, we combine cell viability assays, thioflavin T (ThT) aggregation kinetics, circular dichroism (CD), transmission electron microscopy (TEM), and atomistic molecular dynamics (MD) simulations to investigate how microwave-assisted Epigallocatechin gallate (EGCG) remodels Aβ42 aggregates. We show that microwave exposure markedly enhanced EGCG-mediated cytoprotection in BV2 microglial cells while concurrently suppressing the formation of canonical ThT-responsive amyloid species. MD simulations revealed that oscillating electric fields promote a constrained, interface-selective remodeling of protofibrillar-like aggregates rather than catastrophic depolymerization. In the initial trajectory pair, field assistance redistributed EGCG contacts across more surface residues, accompanied by reduced overall and hydrophobic protein-only solvent-accessible surface area. At a key hydrophobic interface identified by contact-occupancy analysis, the combined treatment decreased local water density and solvent accessibility, indicating reduced local hydration. We define this collective surface state- characterized by expanded EGCG coverage, reduced hydrophobic exposure, and diminished solvent accessibility - as interfacial passivation. Moreover, simulation analysis revealed that the field-assisted EGCG adsorption state remains stable for at least 500 ns after field removal, suggesting that the electric field facilitates formation of a kinetically stable surface-bound configuration. Together, these findings support field-assisted interfacial passivation as a possible mechanism for amyloid modulation and suggest that passivating toxicity-relevant aggregate surfaces, rather than achieving complete depolymerization, may represent a promising therapeutic strategy.},
}

@article {pmid42860522,
year = {2026},
author = {Shiferaw, TG and Sarkar, S and Baker, KM and Wooldridge, RS and Binfet, HM and Prozapas, VN and Ogbu, CP and Schepmoes, AA and Attah, IK and Niemeyer, CS and Sprenger, KG and Hassell, JE and Eckel, RH and Melchior, JT and Bruce, KD},
title = {ApoE lipidation state directs immunometabolic reprogramming of human microglia.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71882},
pmid = {42860522},
issn = {1552-5279},
support = {R01AG079217-01/NH/NIH HHS/United States ; R01NS125591/NS/NINDS NIH HHS/United States ; T32 2T32DK120521-06//Strategic Infrastructure for Research Committee/ ; },
mesh = {Humans ; *Microglia/metabolism ; *Apolipoprotein E4/metabolism ; *Apolipoproteins E/metabolism ; *Lipid Metabolism ; Metabolic Reprogramming ; Mitochondria/metabolism ; Alzheimer Disease/metabolism ; *Apolipoprotein E3/metabolism ; Lipid Droplets/metabolism ; },
abstract = {INTRODUCTION: ApoE ε4 is the strongest genetic risk factor for Alzheimer's disease (AD). Emerging evidence suggests that ApoE4 increases AD risk by disrupting microglial metabolism and function. However, whether ApoE lipidation state contributes to microglial dysfunction remains poorly understood.

METHODS: Human microglia were treated with lipid-free (LF) or lipid-bound ApoE3 or ApoE4. Label-free, live-cell holotomography and global proteomics were used to assess isoform- and lipidation-specific effects on lipid droplet (LD) dynamics, mitochondrial morphology, and microglial phenotype.

RESULTS: ApoE4 treatment resulted in fewer but enlarged LDs and increased mitochondrial fragmentation compared to ApoE3, effects that were enhanced by lipid-bound ApoE4. Proteomic analyses revealed a strong type I interferon response in cells exposed to LF-ApoE, which was exacerbated by LF-ApoE4.

DISCUSSION: These findings indicate that lipid-bound ApoE4 drives metabolic reprogramming, whereas LF-ApoE4 promotes inflammatory signaling, identifying ApoE lipidation as a critical modifier of ApoE4-associated AD risk.},
}

Humans
*Microglia/metabolism
*Apolipoprotein E4/metabolism
*Apolipoproteins E/metabolism
*Lipid Metabolism
Metabolic Reprogramming
Mitochondria/metabolism
Alzheimer Disease/metabolism
*Apolipoprotein E3/metabolism
Lipid Droplets/metabolism

@article {pmid42861699,
year = {2026},
author = {Exalto, LG and van Alphen, JL and Barkhof, F and Teunissen, C and Vijverberg, EGB and Aarsland, D and Lemstra, AW},
title = {Dementia with Lewy bodies and amyloid pathology: Eligible for anti-amyloid treatment or not?.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71907},
pmid = {42861699},
issn = {1552-5279},
mesh = {Humans ; *Lewy Body Disease/drug therapy/pathology ; *Alzheimer Disease/drug therapy/pathology ; *Amyloid beta-Peptides/metabolism ; },
abstract = {In the future, treatment of dementia will be personalized, targeted to contributing pathologies, rather than the clinical syndrome. Anti-amyloid drugs for Alzheimer's disease are the first approved drugs; however, the impact of co‑pathology on the treatment effects remains incomplete. Currently, only patients with a clinical diagnosis of Alzheimer's disease are eligible for these new drugs, but could they also be beneficial when amyloid is present in other neurodegenerative diseases? For example, roughly 50% of patients with dementia with Lewy bodies are amyloid-positive. In this perspective, we discuss the theoretical benefits and challenges of anti-amyloid drugs in patients with a clinical diagnosis of dementia with Lewy bodies and concomitant Alzheimer's disease pathology. We show that a significant portion of newly diagnosed dementia with Lewy bodies patients could be eligible. We advocate for the systematic collection of efficacy and safety data using innovative strategies to achieve adequate statistical power.},
}

Humans
*Lewy Body Disease/drug therapy/pathology
*Alzheimer Disease/drug therapy/pathology
*Amyloid beta-Peptides/metabolism

@article {pmid42861801,
year = {2026},
author = {Alpana, and Dewangan, HK},
title = {Crossing the Blood-brain Barrier: Emerging Nanotechnological Approaches for Neurodegenerative Disease Therapy.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026454704261001071449},
pmid = {42861801},
issn = {1875-5739},
abstract = {Neurodegenerative disorders such as Parkinson's Disease (PD), Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's Disease (HD) are characterized by progressive neuronal degeneration and severe therapeutic limitations due to the Blood-Brain Barrier (BBB). Recent advances in nanotechnology have enabled the development of nanoscale drug delivery systems capable of improving BBB penetration and enhancing therapeutic efficacy. This review discusses recent progress in Lipid Nanoparticles (LNPs), polymeric nanoparticles, exosomes, magnetic nanoparticles, gold nanoparticles, graphene quantum dots, and RNAloaded nanocarriers for brain-targeted delivery. Special emphasis is placed on receptor-mediated transcytosis, intranasal delivery, magnetic targeting, and ionizable lipid nanoparticle systems for nucleic acid delivery. Recent nanoformulations including curcumin-loaded nanoparticles, siRNA- loaded lipid nanoparticles, dopamine-loaded liposomes, and lactoferrin-functionalized polymeric nanoparticles are critically compared based on BBB penetration, therapeutic efficacy, toxicity, and translational potential. Furthermore, current clinical challenges including nanotoxicity, pharmacokinetics, large-scale manufacturing, and regulatory barriers are discussed. Nanotechnology- based therapeutics represent a promising strategy for improving diagnosis and treatment of neurodegenerative disorders and may facilitate the future development of precision nanomedicine.},
}

@article {pmid42862019,
year = {2026},
author = {Stögmann, E and Haider, L and Leinkauf, J and Nakuz, T and Untersteiner, H and Farr, C and Silvaieh, S and Parvizi, T and Wurm, R and Kasprian, G and Berger, T and Gelpi, E and Sieczkowski, EB},
title = {Progressive Amyloid-Related Imaging Abnormalities After Discontinuation of Lecanemab in Early Alzheimer Disease in an APOE ε2/ε4 Carrier.},
journal = {European journal of neurology},
volume = {33},
number = {10},
pages = {e70779},
pmid = {42862019},
issn = {1468-1331},
mesh = {Humans ; *Alzheimer Disease/drug therapy/genetics/diagnostic imaging ; Apolipoprotein E4/genetics ; Magnetic Resonance Imaging ; Disease Progression ; *Antibodies, Monoclonal, Humanized/adverse effects ; Apolipoprotein E2/genetics ; Female ; Heterozygote ; Brain/pathology/diagnostic imaging ; Male ; },
abstract = {BACKGROUND: Amyloid-related imaging abnormalities (ARIA) are the most relevant adverse events associated with anti-amyloid therapies in Alzheimer's disease.

METHODS: We report a case of progressive ARIA after discontinuation of lecanemab in a patient with early-onset Alzheimer's disease carrying the rare APOE ε2/ε4 genotype.

RESULTS: After two infusions, mild ARIA-edema (ARIA-E) and ARIA-hemorrhage (ARIA-H) were detected on routine MRI, prompting treatment interruption. Despite partial radiologic regression, follow-up MRI 8 weeks after discontinuation demonstrated marked progression with multifocal ARIA-H displaying as superficial siderosis, while the patient remained clinically asymptomatic. Corticosteroid treatment was initiated and lecanemab permanently discontinued.

CONCLUSION: This case highlights that severe ARIA may progress beyond active treatment exposure and emphasizes the importance of continued MRI surveillance even after therapy cessation. Furthermore, the APOE ε2/ε4 genotype may represent a distinct risk factor for cerebral amyloid angiopathy-related vascular fragility and hemorrhagic ARIA.},
}

Humans
*Alzheimer Disease/drug therapy/genetics/diagnostic imaging
Apolipoprotein E4/genetics
Magnetic Resonance Imaging
Disease Progression
*Antibodies, Monoclonal, Humanized/adverse effects
Apolipoprotein E2/genetics
Female
Heterozygote
Brain/pathology/diagnostic imaging
Male

@article {pmid42862052,
year = {2026},
author = {Unnikrishnan, B and Anand, A and Fang, CN and Wu, SM and Wang, CC and Huang, CC and Chu, HW and Chang, HT},
title = {Carbon dot-based nanomaterials in neurodegeneration: addressing neurobiological barriers and targeting challenges.},
journal = {Chemical communications (Cambridge, England)},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6cc03262a},
pmid = {42862052},
issn = {1364-548X},
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, represent a major global health challenge due to their progressive nature and limited therapeutic options. One of the primary obstacles to treating these disorders is the blood-brain barrier (BBB), which restricts the delivery of most therapeutic agents into the central nervous system. In recent years, carbon-based nanomaterials, particularly carbon dot (CD) nanostructures, have emerged as promising platforms for neurological applications owing to their ultrasmall size, BBB-crossing ability, and anti-inflammatory and neuroprotective properties, in addition to tunable surface chemistry, strong photoluminescence, and favorable biocompatibility. This review provides a comprehensive overview of recent research developments in the application of CD-based nanomaterials, including carbon nanodots, carbon quantum dots, graphene quantum dots, and carbon polymer dots, for the potential treatment of neurodegenerative diseases. The synthesis strategies and carbonization approaches used to produce these carbon nanomaterials are discussed, along with their physicochemical properties relevant to neurobiological applications, such as particle size, surface functionalization, heteroatom doping, optical properties, and stability in biological environments. Furthermore, the mechanisms by which CD-based nanomaterials can traverse the BBB are examined, including receptor-mediated and adsorptive-mediated transcytosis pathways. In addition, their applications are discussed, with particular focus on their roles in bioimaging, biosensing, inhibition of pathological protein aggregation, antioxidative activity, and targeted drug delivery. Finally, key challenges related to toxicity, biodistribution, large-scale synthesis, and clinical translation are discussed, along with future perspectives for the development of multifunctional theranostic platforms. Overall, use of CD-based nanomaterials represents a promising emerging strategy for overcoming neurobiological barriers and enabling the development of next-generation nanotherapeutics for the management of neurodegenerative diseases.},
}

@article {pmid42863347,
year = {2026},
author = {Zhao, J and Qu, L and Guan, H and Che, H and Shi, F and Yang, Y},
title = {Immunosenescence as a modifiable driver of neurodegenerative diseases: Pathways and multidimensional emerging strategies for Alzheimer's and Parkinson's diseases.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {6},
pages = {e01096},
doi = {10.1016/j.neurot.2026.e01096},
pmid = {42863347},
issn = {1878-7479},
abstract = {Immunosenescence represents a core upstream driver of Alzheimer's disease (AD) and Parkinson's disease (PD), exerting its pathological effects through four mechanistically interconnected cascades: chronic inflammatory imbalance mediated by the senescence-associated secretory phenotype (SASP), oxidative stress arising from immune-metabolic reprogramming, protein homeostasis dysfunction caused by autophagy-lysosomal failure, and disrupted neuro-immune crosstalk secondary to breakdown of central nervous system (CNS) immune privilege. Current clinical practice remains largely constrained to neurotransmitter-based symptomatic management, which can neither arrest upstream pathological progression nor restore lost neuronal populations. Emerging intervention strategies targeting immunosenescence, including senolytic agents, antioxidant and metabolic modulators, autophagy restoration, and precision-targeted nanocarrier delivery, have demonstrated substantial capacity to delay disease progression in preclinical and early clinical investigations. These strategies act through selective clearance of senescent immune cells, remodeling of the neuroinflammatory microenvironment, and restoration of cellular quality-control mechanisms. The multidimensional treatment strategy approaches from the perspectives of artificial intelligence (AI) guided target discovery, nanocarrier engineering, and gut microbiota intervention to simultaneously address multiple nodes in the immunosenescence network, thereby overcoming the inherent limitations of single-target strategies. This review consolidates current mechanistic evidence and translational data to establish immunosenescence as an actionable therapeutic target and to provide a conceptual framework for precision disease-modifying therapy in AD and PD.},
}

@article {pmid42856312,
year = {2026},
author = {Mukherjee, S and Barthélemy, NR and Atri, T and Li, Y and Yen, D and He, Y and Coyle, R and Ovod, V and Franklin, EE and Xiong, C and Wang, G and Xu, J and Farsad, H and Mummery, CJ and Masters, CL and Sanchez-Valle, R and Masellis, M and Hsiung, GR and Guthier, S and Lah, JJ and Berman, SB and Roberson, ED and Surti, G and Honig, LS and Clarnette, R and Vitali, P and Ringman, J and Bird, TD and Brooks, WS and Fox, NC and Suzuki, K and Black, SE and Levin, J and Farlow, MR and Chhatwal, J and Aggarwal, NT and Jucker, M and Frosch, MP and Kofler, JK and White, C and Keene, CD and Chen, J and Glass, J and Gearing, M and Ryan, NS and Aguillón, D and Supnet-Bell, C and Gordon, BA and Benzinger, TLS and Sims, J and Yaari, R and Bittner, T and Klein, G and Delmar, P and Morris, JC and Llibre-Guerra, J and Clifford, DB and Karch, CM and McDade, E and Perrin, RJ and Bateman, RJ and , and , },
title = {Gantenerumab reduces brain amyloid-β proteoforms: Biochemical evaluation in dominantly inherited Alzheimer disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.22.26363432},
pmid = {42856312},
abstract = {UNLABELLED: Therapeutic strategies targeting amyloid-β (Aβ) in Alzheimer disease (AD) include antibodies directed against fibrillar amyloid plaques or soluble amyloid-β (Aβ) species, yet how these approaches reshape brain pathology remains poorly understood. Postmortem neuropathological assessment is crucial for evaluating the degree of Aβ removal, providing information and context that fluid biomarkers and positron emission tomography (PET) alone cannot, and guiding development of more effective disease modifying therapies for AD. In this study, using high resolution mass spectrometry we quantitatively measured Aβ and tau proteoforms in postmortem brain tissue homogenates to evaluate the impact of long-term treatment with anti-Aβ monoclonal antibodies gantenerumab or solanezumab in a clinical trial of dominantly inherited Alzheimer disease (DIAD). Symptomatic DIAD participants who had been treated for ∼ 4 years with anti-Aβ monoclonal antibodies (gantenerumab, n=4 or solanezumab, n=4) were compared with untreated, symptomatic DIAD mutation carriers (n=40) and with age-relevant non-DIAD controls with modest or no plaque pathology (n=18). Consistent with antemortem Aβ-PET findings in the clinical trial, gantenerumab-treated participant samples showed significantly lower levels of specific Aβ proteoforms (Aβ 42 , Aβ 40) in the insoluble plaque associated pool (range: 60-80 % reduction); they also showed lower levels of post-translationally modified Aβ proteoform Aβ 3pGlu in both the insoluble and soluble pool, compared to untreated DIAD participants, but without reaching the levels found in non-DIAD controls. Samples from gantenerumab-treated participants also showed regionally lower amounts of insoluble phosphorylated tau species (pT181, pT205, pT208) and MTBR tau species (354-369, 306-317, 299-317) without apparent differences in insoluble total tau levels. In contrast, brain tissue samples from solanezumab-treated participants did not show significant differences overall in soluble or insoluble levels of Aβ and tau proteoforms in comparison to those from non-treated DIAD individuals. These findings support that amyloid targeting treatment (ATT) with gantenerumab, an antibody that targets fibrillar Aβ, can remove insoluble Aβ from the DIAD brain and also mitigate "downstream" biochemical and pathophysiological changes associated with AD.

KEY SUMMARY: Question: How do amyloid targeting treatments (ATT) affect the Alzheimer disease (AD)-related brain pathologies of soluble and aggregated amyloid-β and tau proteoforms in postmortem tissue?Background: Extracellular amyloid plaques and neurofibrillary tangles (NFTs) are the primary pathological hallmarks of AD. For the past three decades, active and passive immunization against cerebral amyloid-β (Aβ) has constituted one of the primary avenues of disease-modifying intervention in AD. Recently, passive immunizations using anti-Aβ targeting antibodies have demonstrated slowing of cognitive decline in sporadic AD and possibly in dominantly inherited AD (DIAD). In these clinical trials, target engagement has been inferred from Aβ-positron emission tomography (PET) and/or biofluid biomarkers during life. However, to confirm evidence of target engagement more directly, identify which pathological proteoforms are affected, quantify the dose dependent treatment effects of these treatments, and begin to evaluate their putative downstream effects on AD pathophysiology, quantitative biochemical comparisons of amyloid plaques and tau pathology (soluble and insoluble Aβ and tau species) in postmortem brain tissue of treated and untreated AD are needed.Findings: In this study, using high resolution mass spectrometry we measured the soluble and insoluble Aβ and tau proteoforms in the postmortem brain tissue homogenates from DIAN-TU-001 trial participants who were symptomatic and had been treated for ∼ 4 years with gantenerumab (n=4) or solanezumab (n=4), two antibodies that bind to insoluble and soluble Aβ, respectively. Intervals between treatment discontinuation and death ranged from 5 months to 3 years. Comparisons were made with postmortem brain tissue samples from untreated, symptomatic DIAD participants of the DIAN-Obs study (n=40) and from age-relevant, cognitively normal, non-DIAD controls with or without only modest burdens of diffuse Aβ plaques (n=18). Consistent with antemortem Aβ-PET findings in the clinical trial, gantenerumab significantly decreased specific Aβ (Aβ 42 , Aβ 40) proteoforms in the insoluble plaque associated pool (range: 60-80% reduction) compared to the untreated DIAD participants, but without reaching the levels found in the non-DIAD controls. Samples from gantenerumab treated participants also showed significantly lower amount of post-translationally modified Aβ (Aβ 3pGlu) and regionally lower insoluble phosphorylated tau species (pT181, pT205 and pT208), without apparent differences in insoluble total tau levels. In contrast, solanezumab treatment did not show significant effect on the soluble or insoluble levels of Aβ and tau proteoforms in comparison to samples from non-treated DIAD individuals. Significance: These findings support that ATT with gantenerumab, an antibody that targets fibrillar Aβ, can remove insoluble Aβ from the DIAD brain and also mitigate "downstream" biochemical and pathophysiological changes associated with AD.},
}

@article {pmid42856359,
year = {2026},
author = {Petrican, R and Fornito, A},
title = {Alignment with sex-typical brain architecture: Links to mood pathology, sex hormones and transcriptomics of neurodegenerative conditions.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.27.754773},
pmid = {42856359},
issn = {2692-8205},
abstract = {Understanding the mechanisms that underpin the pervasive sex bias in risk for specific psychiatric and neurodegenerative conditions could substantially advance efforts promoting personalized medicine. As a first step towards addressing this issue, we applied imaging transcriptomics and multivariate analysis techniques to data from an adolescent sample enriched in anxiety/depression cases, a child sample enriched in attention deficit hyperactivity disorder (ADHD) cases, and adult patients with treatment resistant major depressive disorder (MDD). We tested whether, across sexes, alignment with female-typical, rather than male-typical, patterns of neural functional connectivity (FC) would relate to a diagnosis (adolescent sample) or severity of symptoms (adult sample) associated with internalizing disorders, which tend to be more often diagnosed in females. To provide preliminary evidence on its functional specificity, we compared the sex-aligned FC profile that distinguished neurotypical adolescents from those diagnosed with depression/anxiety against the sex-aligned FC patterns that distinguished neurotypical children from those diagnosed with ADHD. All the analyses controlled for age within each sample and sex. Finally, we examined the spatial overlap between the sex-aligned FC profile linked to an internalizing diagnosis in adolescence and the transcriptomic maps of genes that show sex-dependent dysregulation in neurodegenerative conditions. Across sexes, increasing alignment with female-typical FC patterns, from sensory-perceptual to default mode regions, discriminated between typically developing and anxious/depressed teens and tracked longitudinal fluctuations in depressive symptoms within adult MDD patients. The identified internalizing-related gradient showed a negative correlation with risk for ADHD in the child sample. The brain regions most strongly aligned with female-, rather than male-, typical FC in depression/anxiety overlapped the spatial expression profiles of genes linked to gonadal hormone synthesis, as well as genes dysregulated in female autism spectrum disorder (ASD) and male neurodegenerative conditions, specifically, Alzheimer's Disease (AD), Huntington's Disease (HD) and Multiple Sclerosis (MS). The brain areas most strongly aligned with male-typical, rather than female-typical, FC patterns overlapped the transcriptomic maps of genes related to androgen and estrogen receptors, as well as of genes dysregulated in male ASD and female neurodegenerative conditions (i.e., AD, HD, MS). Our results raise the possibility that the link between mood pathology and neurodegeneration could reflect a partial, regional reversal of sex-normative functional brain profiles.},
}

@article {pmid42856599,
year = {2026},
author = {Krishingner, T and Fausett, SR},
title = {A New Soaking Protocol to Live Stain C. elegans with Proteostat Dye Reveals Global Patterns of Stress-Induced Protein Aggregation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.30.755777},
pmid = {42856599},
issn = {2692-8205},
abstract = {Protein aggregates are a diverse array of intra- and extracellular structures containing misfolded proteins with limited macromolecular movement. Protein aggregation is induced by aging and cellular stress and is a hallmark of neurodegenerative diseases including Huntington's, Alzheimer's, and Parkinson's. Fluorescent tools to visualize global protein aggregation in whole organisms are, therefore, important for screening genes and compounds that may reduce or alter protein aggregation in connection with improved health outcomes. Fluorescent probes that report low fluidity structures in cells, such as molecular rotor dyes, are gaining popularity and overcome certain limitations of targeted markers such as tagged proteins or antibodies. However, permeability has been a key barrier preventing widespread use of such probes in whole organisms, including in C. elegans . To achieve visualization of non-specific protein aggregates in whole C. elegans nematodes without the need for strain engineering, we have developed a simple soaking protocol. Our protocol overcomes the permeability limitations of the commercially available molecular rotor dye, Proteostat, enabling widespread labeling of protein aggregates in live and post-fixed worms. Here, we present our novel approach and demonstrate quantification of protein aggregates in multiple tissues to detect differences in protein aggregation due to both genotype and treatment effects. We also outline anticipated future applications for this protocol, including its adaptation for other dyes, as well as limitations and special considerations for its use.},
}

@article {pmid42856786,
year = {2026},
author = {Li, X and Qi, H and Zhang, X and Jin, X and Xu, J and Ma, J},
title = {Comparative effects of six exercise modalities on global cognitive function in Alzheimer's disease, Parkinson's disease, and mild cognitive impairment: a systematic review and network meta-analysis.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1877537},
pmid = {42856786},
issn = {1664-2295},
mesh = {Humans ; *Cognitive Dysfunction/therapy/psychology/rehabilitation ; *Parkinson Disease/therapy/psychology/rehabilitation ; *Alzheimer Disease/therapy/psychology/rehabilitation ; *Exercise Therapy/methods ; *Cognition/physiology ; Cognitive Enhancement ; *Exercise ; },
abstract = {BACKGROUND: Alzheimer's disease (AD), Parkinson's disease (PD), and mild cognitive impairment (MCI) are commonly accompanied by cognitive decline. Although exercise is recommended as a non-pharmacological strategy, the comparative effects of different exercise modalities on global cognition remain uncertain.

OBJECTIVE: To compare six exercise modalities-aerobic exercise (AE), mind-body exercise (MBE), resistance training (RT), multi-component exercise (MCE), flexibility training (FT), and functional training (FTr)-for global cognitive function in people with AD, PD, or MCI, and to explore dose-related associations.

METHODS: PubMed, Embase, the Cochrane Library, and Web of Science were searched from inception to January 26, 2026. Randomized controlled trials (RCTs) were synthesized using a frequentist random-effects network meta-analysis (NMA) with standardized mean differences (SMDs) and 95% confidence intervals (CIs). Treatment rankings were summarized using SUCRA. Subgroup analyses, meta-regression, diagnosis-related sensitivity analyses, and CINeMA certainty assessments were also performed.

RESULTS: Twenty-eight trials involving 1,993 participants were included. Compared with control group (CG), AE [SMD = 0.47, 95% CI (0.18, 0.77)], MBE [SMD = 0.79, 95% CI (0.46, 1.11)], RT [SMD = 1.50, 95% CI (0.77, 2.23)], MCE [SMD = 0.83, 95% CI (0.26, 1.40)], and FTr [SMD = 0.83, 95% CI (0.13, 1.53)] improved global cognition, whereas FT showed no clear effect [SMD = -0.20, 95% CI (-1.27,0.87)]. RT ranked first, followed by MCE, FTr, MBE, AE, and FT. Heterogeneity was substantial (τ[2] = 0.23; I[2] = 80%), although no statistically significant global incoherence was detected. RT remained first after the exclusion of AD, PD, or MCI studies. Studies lasting more than 12 weeks, delivered 3-5 times per week, and using sessions of 31-60 min showed favorable pooled effects, but subgroup interaction tests and meta-regression were not significant. Certainty of evidence ranged from low to very low.

CONCLUSION: AE, MBE, RT, MCE, and FTr may improve global cognition in people with AD, PD, or MCI. RT showed the largest effect estimate and the most favorable ranking. However, substantial heterogeneity and sparse evidence for several modalities limit firm conclusions. Exercise selection should be individualized, and dose-related findings require confirmation in adequately powered comparative trials.},
}

Humans
*Cognitive Dysfunction/therapy/psychology/rehabilitation
*Parkinson Disease/therapy/psychology/rehabilitation
*Alzheimer Disease/therapy/psychology/rehabilitation
*Exercise Therapy/methods
*Cognition/physiology
Cognitive Enhancement
*Exercise

@article {pmid42857403,
year = {2026},
author = {Agosta, F and Cecchetti, G and Ghirelli, A and Spinelli, EG and Rugarli, G and Pisano, S and Coraglia, F and Gajate, AMS and Vezzulli, P and Calloni, S and Canu, E and Castelnovo, V and Gilioli, A and Tripodi, C and Freri, F and Bianchi, A and Panzacchi, A and Pepe, G and Falini, A and Chiti, A and Filippi, M},
title = {Residualized occipital amyloid burden and plasma biomarker profiles in relation to ARIA-E during anti-amyloid treatment.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70401},
pmid = {42857403},
issn = {2352-8729},
abstract = {INTRODUCTION: Amyloid-related imaging abnormalities with edema (ARIA-E) represent the main safety concern of anti-amyloid monoclonal antibodies. Whether regional amyloid topology refines ARIA-E risk in real-world practice remains unclear.

METHODS: We analyzed 31 treatment courses in early Alzheimer's disease under European Medicines Agency labeling. Residualized occipital amyloid burden was defined as observed occipital standardized uptake value ratio (SUVR) minus occipital SUVR predicted from global composite SUVR in an expanded baseline positron emission tomography derivation sample (n = 53). Associations with ARIA-E and baseline plasma biomarkers were assessed.

RESULTS: ARIA-E occurred only in the elevated occipital amyloid group: 4/13 treatment courses, versus 0/18 low or comparable courses (Fisher exact p = 0.055). All ARIA-E events involved posterior regions. The elevated pattern showed higher baseline glial fibrillary acidic protein (GFAP), phosphorylated tau (p-tau)181, and p-tau217 levels, whereas amyloid beta 42/40 did not differ between groups. A GFAP + p-tau217 model showed exploratory discrimination of the elevated phenotype (area under the curve: 0.76).

DISCUSSION: Disproportionate occipital amyloid burden may identify a biologically vulnerable subgroup requiring validation in larger cohorts.},
}

@article {pmid42857419,
year = {2026},
author = {Ghirelli, A and Cecchetti, G and Spinelli, EG and Samanes Gajate, AM and Rugarli, G and Pisano, S and Zamboni, IAL and Canu, E and Castelnovo, V and Sibilla, E and Gilioli, A and Tripodi, C and Freri, F and Panzacchi, A and Pepe, G and Chiti, A and Filippi, M and Agosta, F},
title = {Regional amyloid-PET clearance dynamics and anti-Aβ monoclonal antibody therapy: a preliminary real-world study.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70448},
pmid = {42857419},
issn = {2352-8729},
abstract = {INTRODUCTION: Amyloid positron emission tomography (PET) is the reference biomarker for treatment target engagement in anti-amyloid beta (Aβ) therapies in early symptomatic Alzheimer's disease (AD), yet global metrics may mask a regional heterogeneity of amyloid clearance.

METHODS: We report real-world longitudinal amyloid-PET data from 26 patients treated with lecanemab or donanemab for 6 months. Global Centiloids and regional standardized uptake value ratios (SUVRs) were quantified at baseline and 6 months and examined according to treatment, clinical diagnosis, and clinical stage.

RESULTS: Amyloid removal was regionally heterogeneous. Patients with mild cognitive impairment showed greater cortical amyloid reduction than those with mild dementia, while early- and late-onset AD exhibited comparable clearance. Frontal, anterior cingulate, and parietal regions showed the largest SUVR reductions, whereas the occipital cortex and temporal mesial cortex were consistently spared, including in patients reaching global amyloid-PET negativity.

DISCUSSION: Early amyloid clearance following anti-amyloid treatment is regionally heterogeneous and incompletely captured by global PET measures.},
}

@article {pmid42857600,
year = {2026},
author = {Moughamian, AJ and La Vallee, L and Kile, S and Urban, T and Momii, A and Manifield, M and Minton, J},
title = {The Advanced Therapeutics for Alzheimer's Disease Review Board: A multidisciplinary model to facilitate safe access to amyloid-targeting therapies in general neurology across the Sutter Health system.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70479},
pmid = {42857600},
issn = {2352-8729},
abstract = {Amyloid-targeting therapies (ATTs) require workup and monitoring that some general neurologists are uncomfortable with. Sutter Health treats over 3.5 million patients with more than 100 neurologists, but only 5 cognitive specialists. We developed the Advanced Therapeutics for Alzheimer's Disease (ATAD) Review Board, a system-wide model to address the shortage of specialists while enhancing safe access to ATTs across the health system. The ATAD Review Board comprises cognitive specialists, a neuroradiologist, a pharmacist, and a registered nurse program manager. Neurologists submit cases to the board for appropriate patient selection and re-review of cases with side effects. We reviewed 447 cases from 51 neurologists and 77% were eligible for treatment. The annual volume increased 148% in 2025. Total amyloid-related imaging abnormality rate was 17.4% for lecanemab and 28.8% for donanemab. We describe a system-wide review board model that supported ATT prescribing by general neurologists and expanded safe access to ATTs across a large integrated health system.},
}

@article {pmid42857741,
year = {2026},
author = {Shimazu, T and Hoshino, E and Nakaseko, M and Homma, K and Suzuki, S and Horikoshi, K and Maruki, Y},
title = {Caregiver-Reported Behavioral Changes After Donepezil Transdermal Patch Therapy in Alzheimer's Disease: An Exploratory Real-World Network Analysis.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {637015},
pmid = {42857741},
issn = {1176-6328},
abstract = {PURPOSE: To characterize caregiver-reported behavioral changes after donepezil transdermal patch therapy and to examine the descriptive connectivity of co-occurring improvements in patients with Alzheimer's disease (AD).

PATIENTS AND METHODS: This retrospective, single-center observational study included 26 patients meeting the 2011 National Institute on Aging-Alzheimer's Association criteria for probable AD dementia. Approximately 2-4 months after patch initiation, caregivers rated nine behavioral domains using routine, non-validated single-item change assessments as improved, unchanged, or worsened relative to the pre-treatment state. A descriptive co-improvement network was used solely to summarize pairwise co-occurrence of binary improvement indicators using phi-coefficients and observed strength centrality. Because of the small sample and sparse binary events, all network measures were treated as sample-specific descriptive quantities rather than inferential estimates.

RESULTS: The most frequently improved domains were smiling/positive affect (12/26, 46.2%), calmness (9/26, 34.6%), and night-time sleep (8/26, 30.8%). Calmness had the highest observed strength centrality (2.467), followed by grooming behavior (2.059), hobbies/interests (2.009), and housework/instrumental activities of daily living (1.938). Calmness remained the highest-strength node in all 26 leave-one-participant-out sensitivity analyses. No treatment discontinuations or serious adverse events were documented.

CONCLUSION: Caregiver-perceived calmness, assessed as a single non-validated change item, was the most highly connected domain in this small descriptive co-improvement network. The findings are exploratory and do not establish treatment efficacy, a validated agitation-related outcome, temporal direction, or mechanism. Prospective studies using standardized behavioral measures are needed.},
}

@article {pmid42857961,
year = {2026},
author = {Chandrakar, K and Panday, A and Patel, D and Poleboina, S},
title = {Neuroprotective effects of lithium and caffeic acid co-loaded liposomes in diabetes-induced Alzheimer's disease: association with GSK-3β and β-catenin.},
journal = {Nanomedicine (London, England)},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/17435889.2026.2743276},
pmid = {42857961},
issn = {1748-6963},
abstract = {AIM: To investigate the therapeutic effects of co-loaded lithium (Li) and caffeic acid (CA) liposomes in diabetes-induced Alzheimer's disease rats by improving cognitive dysfunction and attenuating neurodegeneration through the modulation of β-catenin/GSK-3β signaling.

METHODS: Li- and CA-co-loaded liposomes were prepared by the ethanol injection method and characterized. A diabetes-induced Alzheimer's disease model was established in male Wistar rats using a high-fat diet followed by low-dose streptozotocin (35 mg/kg) administered intraperitoneally. Li- and CA-co-loaded liposomes were given via the same route every day for 4 weeks. At the end of the experiment, the animals were sacrificed, and various biochemical and oxidative stress parameters, histopathological assessments, and ELISA analyses were performed.

RESULTS: Dual-drug-loaded Li and CA liposomal treatment significantly improved cognitive function, ameliorated metabolic dysfunction, and reduced oxidative stress by restoring antioxidant enzyme levels. Additionally, liposomes attenuated nitrite, acetylcholinesterase, and amyloid-β levels in diabetes-induced Alzheimer's rats. Histopathological assessment confirmed marked neuroprotective and pancreatic protective effects. Further, at a molecular level, Li and CA liposomal treatment reduced the expression of GSK-3β and increased the expression of β-catenin levels in rats.

CONCLUSION: This study provides the first evidence demonstrating the therapeutic potential of Li- and CA-co-loaded liposomes in attenuating diabetes‑associated cognitive dysfunction.},
}

@article {pmid42857983,
year = {2026},
author = {Smitasiri, T and Pongpitakmetha, T and Thanprasertsuk, S and Likitjaroen, Y},
title = {Prevalence and impact of cerebral small vessel lesions in mild cognitive impairment and mild dementia due to Alzheimer's disease patients in memory clinic: Preparation for anti-amyloid therapy in Thailand.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261493065},
doi = {10.1177/13872877261493065},
pmid = {42857983},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) raises global concern with its impact on daily living. Anti-amyloid therapy (AAT) are specific treatments used in mild cognitive impairment (MCI) and mild dementia stage of AD (mild AD). Severe cerebral small vessel disease (SVD) lesions such as microbleeds, superficial siderosis, lacunes, white matter hyperintensities are listed as exclusions criteria for AAT. In Thailand, there is no prevalence study of SVD lesions specifically in these patient groups.ObjectiveThe purpose of this study is to report the prevalence of SVD burdens which are excluded in AAT, in MCI and mild AD patients in Thailand.MethodsThe study was carried out at Memory Clinic in King Chulalongkorn Memorial Hospital. Patients with amnestic MCI and mild AD were diagnosed using clinical criteria, cognitive tests and brain MRI. Visual rating scales were used to evaluate SVD burden based on STRIVE-2 criteria. Baseline characteristics and cognitive tests were retrieved from electronic medical records.ResultsThe study involving 102 patients, 73.5% had MCI, and 26.5% had mild AD. Twenty-one individuals (20.6%) had either more than 4 microbleeds, more than 2 lacunes, or Fazekas score of 3. There was no evidence of superficial siderosis. Individuals without microbleeds had a higher TMSE score (25.4 versus 23.5; p = 0.009).ConclusionsAmong patients with MCI and mild AD, 20.6% met the exclusion criteria for AAT, in part of SVD lesions. These findings provide important information for evaluating the cost-effectiveness of AAT, which become a treatment option for Thai AD patients.},
}

@article {pmid42846808,
year = {2026},
author = {Liu, T and Liu, Y and Zhang, Y and Wang, J and Ren, Y and Fu, S and Han, L and Jiang, P and Chen, J and Li, Y and Luo, H},
title = {Peroxisomes in Alzheimer's disease: emerging mechanistic insights and therapeutic opportunities.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1960320},
pmid = {42846808},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) deposition, tau pathology, synaptic injury, neuroinflammation, oxidative stress, and disrupted organellar homeostasis. Peroxisomes maintain lipid and redox balance through very-long-chain fatty acid (VLCFA) β-oxidation, plasmalogen biosynthesis, and reactive oxygen species (ROS) metabolism. This Review evaluates how peroxisomal alterations may modulate APP processing and Aβ clearance, tau kinase/phosphatase balance, neuroinflammation, oxidative stress, and peroxisome-mitochondria crosstalk. We distinguish human correlational evidence from intervention studies in AD models and mechanistic extrapolation from primary peroxisomal disorders. Current evidence supports a context-dependent vulnerability or amplifier model rather than a universal causal pathway. Peroxisome-targeted interventions remain investigational, and no validated biomarker currently identifies an AD subgroup for such treatment.},
}

@article {pmid42847130,
year = {2026},
author = {Adedayo, BC and Oyeleye, IS and Oyelami, OS and Aro, OP and Ojo, OR and Oboh, G},
title = {Aqueous extracts of Phyllanthus amarus leaf mitigate cognitive impairments by enhancing neurotransmitter regulation and antioxidant defense mechanisms.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/17582024.2026.2744198},
pmid = {42847130},
issn = {1758-2032},
abstract = {AIMS: Phyllanthus amarus (PA, P. amarus), commonly known as stonebreaker, has historically been used in traditional medicine for its medicinal attributes. Cognitive impairment continues to pose a major challenge in neurodegenerative disorders, with natural products being extensively explored as potential therapies. This study examined the effects of aqueous leaf extracts P. amarus on cognitive behaviors and neurochemical markers in scopolamine-induced amnesic rats.

MATERIAL AND METHODS: Rats were administered aqueous PA extracts (50 and 500 mg/kg) or donepezil for a duration of 14 days. Cognitive performance was assessed through behavioral tests followed by neurochemical evaluation of cholinesterases (ChEs), monoamine oxidase (MAO), and purinergic enzymes in the cortex and hippocampus of the rats' brains.

RESULTS: Administration of scopolamine impaired learning and memory and disrupted biochemical homeostasis. Treatment with PA extract significantly improved cognitive performance and attenuated scopolamine-induced alterations in neurotransmitter activity and oxidative stress markers.

CONCLUSION: In conclusion, aqueous leaf extracts of PA treatment may provide a new potential alternative for the treatment and prevention of cognitive impairment and neurochemical changes associated with neurotoxic agents, suggesting its potential to ameliorate scopolamine‑induced cognitive impairment and neurochemical alterations, while further studies are required to establish relevance to Alzheimer's disease pathology.},
}

@article {pmid42847220,
year = {2026},
author = {Cancelloni, V and Caso, V},
title = {Aldosterone, the brain, and the blood pressure ceiling: a neurological case for aldosterone synthase inhibitors in resistant hypertension.},
journal = {American journal of hypertension},
volume = {39},
number = {Supplement_1},
pages = {S57-S65},
doi = {10.1093/ajh/hpag091},
pmid = {42847220},
issn = {1941-7225},
mesh = {Humans ; *Hypertension/drug therapy/physiopathology/enzymology/complications ; *Aldosterone/metabolism ; *Cytochrome P-450 CYP11B2/antagonists & inhibitors/metabolism ; *Blood Pressure/drug effects ; Animals ; *Brain/physiopathology/drug effects/enzymology ; *Antihypertensive Agents/therapeutic use/adverse effects ; Drug Resistance ; Renin-Angiotensin System/drug effects ; *Stroke/prevention & control/physiopathology/etiology ; Treatment Outcome ; Mineralocorticoid Receptor Antagonists/therapeutic use ; Risk Factors ; },
abstract = {Hypertension is the leading modifiable risk factor for stroke and a major contributor to cognitive impairment and dementia, with its global burden increasing alongside population aging. Hypertension promotes cerebrovascular damage through endothelial dysfunction, blood-brain barrier disruption, small vessel disease, and accelerated atherosclerosis, all potentially contributing to both ischemic and hemorrhagic stroke risk. These vascular alterations also contribute to neurodegenerative processes, linking hypertension-particularly when present in midlife-to vascular dementia and Alzheimer's disease. Effective blood pressure control (target <130/80 mm Hg) remains central to primary and secondary stroke prevention and is associated with reduced risks of recurrent stroke and cognitive decline. The renin-angiotensin-aldosterone system plays a central role in hypertension-related cerebrovascular injury, with aldosterone excess contributing to vascular inflammation, oxidative stress, and impaired cerebral autoregulation. Resistant hypertension, often driven by aldosterone dysregulation, is associated with increased cardiovascular and neurological risk. Aldosterone synthase inhibitors such as lorundrostat and baxdrostat represent a novel therapeutic approach targeting aldosterone production. Clinical trials demonstrate significant reductions in systolic blood pressure with favorable safety profiles in patients with uncontrolled or resistant hypertension. Although direct evidence for stroke prevention is currently lacking, indirect data suggest that sustained blood pressure reduction and modulation of aldosterone-mediated vascular damage may lower cerebrovascular risk. Aldosterone synthase inhibitors may be particularly relevant in phenotype-driven, personalized treatment strategies for patients with resistant hypertension or suspected aldosterone excess. However, long-term efficacy, safety, and impact on hard outcomes such as stroke and dementia require confirmation in dedicated trials.},
}

Humans
*Hypertension/drug therapy/physiopathology/enzymology/complications
*Aldosterone/metabolism
*Cytochrome P-450 CYP11B2/antagonists & inhibitors/metabolism
*Blood Pressure/drug effects
Animals
*Brain/physiopathology/drug effects/enzymology
*Antihypertensive Agents/therapeutic use/adverse effects
Drug Resistance
Renin-Angiotensin System/drug effects
*Stroke/prevention & control/physiopathology/etiology
Treatment Outcome
Mineralocorticoid Receptor Antagonists/therapeutic use
Risk Factors

@article {pmid42847291,
year = {2026},
author = {Qiao, Z and Zhao, X and Wang, G and Li, S and Lian, T and Ai, L},
title = {PET-based evaluation of short-term amyloid-β clearance and predictive factors in real-world Alzheimer's disease patients treated with lecanemab.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261493063},
doi = {10.1177/13872877261493063},
pmid = {42847291},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a common progressive neurodegenerative disorder. Lecanemab, an anti-amyloid-β (Aβ) monoclonal antibody, is approved for AD treatment, but real-world efficacy and optimal PET application strategies remain incompletely defined.ObjectiveTo investigate lecanemab's Aβ clearance efficacy, identify predictors of response, and optimize PET application strategies.MethodsA retrospective analysis of Aβ PET-positive AD patients treated with lecanemab for 6-8 months. Paired t-tests evaluated standardized uptake value ratios (SUVR) and cognitive changes; Cohen's Kappa assessed visual-quantitative agreement. Exploratory analyses included partial correlation, regression, and Fisher's exact test.ResultsThirty-eight patients were included. Statistically significant Centiloid (CL) reduction occurred post-treatment (mean difference = 29.39 ± 22.31, p < 0.001), without Mini-Mental State Examination/Montreal Cognitive Assessment or tau PET changes. Twelve patients achieved a CL < 24.1, and 5 were visually negative. Visual-quantitative agreement was fair to poor (positivity Kappa = 0.205; efficacy Kappa = 0.253). Baseline CL, treatment cycles, and SUVRtau were screened by univariate regression (p < 0.05) and entered into a multivariate model (F = 13.693, p < 0.001, adjusted R[2] = 0.507). Baseline CL (standardized-β = 0.594, p < 0.001) and treatment cycles (standardized-β = 0.285, p = 0.022) were independent positive predictors; SUVRtau showed marginal negative association (standardized-β = -0.238, p = 0.052).ConclusionsLecanemab was associated with statistically significant amyloid clearance. Baseline amyloid burden and treatment exposure predicted greater clearance; tau showed attenuating trend. Visual-quantitative discordance supports a hybrid PET pathway: visual screening for inclusivity, serial CL quantification for monitoring, and combined assessment for low-CL patients.},
}

@article {pmid42847294,
year = {2026},
author = {Nakamura, Y and Seiyama, Y and Shimizu, K and Shibasaki, Y and Toda, R and Nakamichi, N and Adachi, J and Hirota, N and Nakai, M and Takahashi, K},
title = {Impact of dementia severity on efficacy of brexpiprazole for agitation in Alzheimer's dementia: A post hoc analysis of a randomized, double-blind, placebo-controlled study in Japan.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261493010},
doi = {10.1177/13872877261493010},
pmid = {42847294},
issn = {1875-8908},
abstract = {BackgroundThe impact of dementia severity on the efficacy of brexpiprazole for agitation associated with Alzheimer's disease in Japanese patients remains unclear.ObjectiveThis post hoc analysis aimed to further examine the efficacy of brexpiprazole with respect to the severity of Alzheimer's dementia (AD), determined using Mini-Mental State Examination (MMSE) score, in a randomized, double-blind, placebo-controlled study conducted in Japanese patients with agitation in AD (AAD).MethodsData from Japanese patients with AAD who received brexpiprazole 1 mg/day or 2 mg/day, or placebo for 10 weeks were analyzed. Changes from baseline in Cohen-Mansfield Agitation Inventory (CMAI) total score were evaluated according to severity of dementia (mild-to-moderate AD: MMSE 11-22; severe AD: MMSE 1-10). Changes from baseline in Clinical Global Impression-Severity of Illness (CGI-S) score were similarly assessed.ResultsAt Week 10, greater improvement was observed primarily with brexpiprazole compared with placebo, whereas efficacy in severe AD was limited with the 1 mg dose. Differences between brexpiprazole and placebo in the mean change from baseline in CMAI total score for mild-to-moderate and severe AD groups were -4.2 (p = 0.0306) and -2.9 (p = 0.2534) for brexpiprazole 1 mg, -7.0 (p = 0.0001) and -7.3 (p = 0.0024) for brexpiprazole 2 mg, respectively. Differences in CGI-S score were -0.3 (p = 0.0598) and -0.4 (p = 0.0762) in brexpiprazole 1 mg, -0.8 (p < 0.0001) and -0.7 (p = 0.0002) in brexpiprazole 2 mg, respectively.ConclusionsBrexpiprazole showed efficacy at the 2 mg dose in Japanese patients, supporting its effectiveness for AAD across AD severities; the effects of the 1 mg dose in severe AD were limited.ClinicalTrials.gov IdentifierNCT03620981 (trial registry name: Brexpiprazole for the Treatment of Patients With Agitation Associated With Dementia of the Alzheimer's Type).Available from https://www.clinicaltrials.gov/study/NCT03620981.},
}

@article {pmid42847732,
year = {2026},
author = {O'shea, DM and Disla, S and Gosling, AE and Valdelamar, GA and Ioana Tolea, M and Galvin, JE},
title = {Limitations of current neuroprotective therapies in dementia with Lewy bodies.},
journal = {Expert review of clinical pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1080/17512433.2026.2742316},
pmid = {42847732},
issn = {1751-2441},
abstract = {INTRODUCTION: Dementia with Lewy bodies (DLB) is characterized by progressive cognitive, neuropsychiatric, motor, autonomic, and sleep impairment. Pharmacological interventions developed with disease-modifying intent have entered clinical testing, but their biological rationale and adequacy of evaluation remain uncertain.

AREAS COVERED: This structured narrative review appraises pharmacological interventions developed with disease-modifying intent in DLB, focusing on biological rationale, central nervous system (CNS) exposure and target engagement, and whether trials adequately tested neuroprotection or altered clinical progression. PubMed/MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched for studies published from January 2023 through 29 July 2026, with trial and registry reconciliation continuing through 30 July 2026. Twelve DLB trials evaluated interventions targeting endosomal signaling, kinase-related proteostasis, autophagy-lysosomal function, cellular bioenergetics, oligomer-associated synaptic injury, or neurotrophic signaling. No completed trial established neuroprotection or disease modification. Interpretation was limited by biological heterogeneity, Alzheimer disease co-pathology, incomplete CNS target-engagement evidence, short treatment duration, small samples, and endpoints unable to distinguish symptomatic effects from altered progression.

EXPERT OPINION: Future trials should prioritize biomarker-supported diagnosis, prospective co-pathology assessment, demonstrated CNS exposure and target engagement, and longer follow-up combining clinical and mechanism-linked outcomes.},
}

@article {pmid42849166,
year = {2026},
author = {Sarwar, S and Mehmood, T and Abbasi, GR},
title = {Region-wise chemometric framework for identifying FTIR functional-group signatures associated with cholinesterase inhibition.},
journal = {Computational biology and chemistry},
volume = {126},
number = {Pt 2},
pages = {109474},
doi = {10.1016/j.compbiolchem.2026.109474},
pmid = {42849166},
issn = {1476-928X},
abstract = {Two key therapeutic targets in the treatment of Alzheimer's disease are acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Understanding the molecular characteristics associated with cholinesterase inhibition is important for the development of new inhibitors. In this study, a chemometric framework integrating Fourier Transform Infrared (FTIR) spectroscopy, Principal Component Analysis (PCA), and region-wise Partial Least Squares Regression (PLSR) was applied to explore spectral-response relationships in newly synthesized flurbiprofen hydrazide and hydrazone derivatives. The dataset comprised 27 compounds with 1868 spectral variables covering the 4000-400 cm[-1] region and experimentally determined AChE and BuChE inhibition activities. Following SNV preprocessing, PCA was used to characterize spectral variability and define five major spectral domains: O-H/N-H, C-H, carbonyl/amide, C-O/C-N, and fingerprint regions. Region-wise PLSR models were evaluated using 5-fold cross-validation based on RMSECV and MAE-CV, with Y-randomization providing an additional assessment of the observed modeling performance. Among the investigated regions, the C-H stretching domain (3000-2800 cm[-1]) showed the most favorable relative cross-validated performance for both AChE (RMSECV = 5.49; MAE-CV = 4.02) and BuChE (RMSECV = 5.09; MAE-CV = 5.13). Y-randomization further supported the response-related performance of the C-H region, particularly for BuChE. Regression coefficient profiles provided additional spectral information for interpreting the response-related variation across the investigated regions. Overall, the FTIR-PCA-PLSR framework provides an interpretable approach for comparative assessment of spectral domains and for generating chemically testable hypotheses regarding cholinesterase inhibition in the investigated flurbiprofen derivative series.},
}

@article {pmid42849557,
year = {2026},
author = {Shrirame, D and Tatode, A and Dabhade, D and Taksande, J and Taksande, B and Kakade, O and Umekar, M},
title = {Intermittent Fasting as a Therapeutic Strategy in Alzheimer's Disease: Understanding of Brain-Derived Neurotrophic Factor Modulation.},
journal = {Physiology & behavior},
volume = {},
number = {},
pages = {115522},
doi = {10.1016/j.physbeh.2026.115522},
pmid = {42849557},
issn = {1873-507X},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease with amyloid-beta (Aβ) plaques, tau tangles, neuroinflammation, and oxidative stress, and it causes cognitive impairment and neuronal loss. The pharmacological treatment is of limited effectiveness, therefore the interest in novel approaches such as intermittent fasting (IF). IF, a nutritional regimen of periodic caloric restriction, has shown a potential to modulate neurodegenerative alterations by metabolic and molecular mechanisms. This review presents the implications of IF in the etiopathogenesis of AD, specifically in controlling brain-derived neurotrophic factor (BDNF). BDNF is a major neurotrophin that plays a key role in synaptic plasticity, neuronal survival, and cognition. Evidence indicates that BDNF is drastically decreased in AD, therefore enhancing disease progression. IF enhances BDNF expression via mechanisms such as improved mitochondrial function, increased ketone body production, and reduced systemic inflammation. Preclinical studies indicate that IF not only upregulates BDNF but also alleviates key AD pathologies, including Aβ deposition and tau hyperphosphorylation. Additionally, clinical data highlight the cognitive benefits of IF and its role in modulating metabolic health, although studies specifically linking IF, BDNF and AD in humans remain limited. This review underscores the need for further research to determine optimal IF protocols and clarify its long-term impact on AD progression. IF's ability to modulate BDNF and other neuroprotective pathways positions it as a promising non-pharmacological intervention for AD management. By bridging metabolic health and neuroprotection, IF offers potential therapeutic synergy for mitigating AD's complex etiopathogenesis.},
}

@article {pmid42850455,
year = {2026},
author = {Padovani, A and Altini, M and Bellelli, G and Bozzali, M and Brignoli, O and Cagnin, A and Cherubini, A and Iannacci, M and Lodi, R and Logroscino, G and Marra, C and Nicora, C and Parretti, S and Sacco, A and Spadin, P and Zappia, M},
title = {Organizing healthcare delivery in the era of disease-modifying therapies for Alzheimer's Disease: an Italian RAND/UCLA consensus.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {11},
pages = {},
pmid = {42850455},
issn = {1590-3478},
mesh = {Humans ; *Alzheimer Disease/therapy/diagnosis ; Italy ; *Delivery of Health Care/organization & administration ; Consensus ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) poses a growing clinical and organizational challenge, requiring coordinated, multidisciplinary care models. In Italy, significant regional variability in resources and access to diagnostic services persists, while the implementation of community-based care models, the expanding role of biomarkers, and the advent of disease-modifying therapies (DMTs) further highlight the need for a more coordinated and equitable dementia care network.

OBJECTIVE: Develop system-level recommendations to optimise the organisation of AD care delivery in Italy in anticipation of DMTs introduction.

METHODS: Using the RAND/UCLA Appropriateness Method, a multidisciplinary panel rated 55 statements across nine domains, evaluating appropriateness in two rounds and priority of implementation in a third round.

RESULTS: Consensus was achieved for all statements, with high appropriateness and priority ratings. The statements outline a regional, network-based model organised across territorial services, Spoke and Hub centres, with formal governance responsible for pathway definition and monitoring. Referral pathways from primary care are based on cognitive and frailty assessment, with non-frail patients referred to Spoke for clinical, neuropsychological and neuroradiological evaluation. Patients potentially eligible for DMTs are referred to Hub centres, where diagnostic confirmation is completed and multidisciplinary teams assess treatment eligibility. When authorised, Hub centres are responsible for DMTs prescription and administration. The statements emphasise the need for standardised neuropsychological and neuroradiological protocols for amyloid-related imaging abnormalities (ARIA) monitoring, alongside the progressive adoption of plasma biomarkers, telemedicine, and structured communication with patients and caregivers.

CONCLUSION: This consensus provides a pragmatic framework to support the reorganisation of AD care in Italy, ensuring that every patient is directed to the most appropriate level of care across a flexible regional network.},
}

Humans
*Alzheimer Disease/therapy/diagnosis
Italy
*Delivery of Health Care/organization & administration
Consensus

@article {pmid42851222,
year = {2026},
author = {Sankar, G and R, I and Umasankar, H},
title = {Therapeutic role of deferasirox loaded niosomes against aluminium-maltolate induced Alzheimer disease: A study in Swiss albino mice.},
journal = {The Indian journal of medical research},
volume = {164},
number = {4},
pages = {550-558},
pmid = {42851222},
issn = {0971-5916},
mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/pathology ; *Deferasirox/administration & dosage ; Mice ; Oxidative Stress/drug effects ; Male ; Humans ; Liposomes/chemistry/administration & dosage ; Brain/drug effects/pathology ; Aluminum/toxicity ; Neuroprotective Agents ; Reactive Oxygen Species/metabolism ; Disease Models, Animal ; Organometallic Compounds/toxicity ; Maze Learning/drug effects ; Aluminum Compounds/toxicity ; Pyrones ; },
abstract = {Background and objectives Aluminium, a common component in underarm deodorants, has been reported to increase oxidative stress when present in the bloodstream, and chronic exposure is considered a potential risk factor for Alzheimer disease. This study investigates the neuroprotective and chelating effects of deferasirox (DFX) and its niosome-based formulation (DFX-NS) against aluminium-maltolate (Almal)-induced neurotoxicity in mice. Methods Thirty male Swiss albino mice were randomly assigned into five groups: Control, Almal, Standard (STD), DFX, and DFX-NS. For 21 d, all groups except the control received Almal to induce neurotoxicity, followed by respective treatments for an additional 21 d. After the treatment period, cognitive function was assessed using behavioral tests such as the Morris Water Maze and Y Maze. An in vitro MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was performed on SH-SY5Y cells to evaluate the neuroprotective potential of DFX. In vivo analyses-including elemental analysis (ICP-MS), histopathology, oxidative stress parameters [Reactive Oxygen Species (ROS), Malondialdehyde (MDA), Catalase (CAT)], urine analysis, and protein estimation (Bradford assay)-were performed on the brain, which was isolated after cervical dislocation. Results The results obtained shows that the Deferasirox has optimum capacity to chelate the aluminium ions in the brains of the Alzheimer-diseased swiss albino mice. Though, the evidence obtained were not fully conclusive, but still the results from the niosomes group shows effective treatment option for the Alzheimer disease caused by the aluminium exposure. Interpretation and conclusions The efficacy of DFX and DFX-NS in reducing aluminium-induced neurotoxicity and oxidative stress in the brain proves that DFX could be a possible candidate for treating Alzheimer's patients linked with metal toxicities.},
}

Animals
*Alzheimer Disease/drug therapy/chemically induced/pathology
*Deferasirox/administration & dosage
Mice
Oxidative Stress/drug effects
Male
Humans
Liposomes/chemistry/administration & dosage
Brain/drug effects/pathology
Aluminum/toxicity
Neuroprotective Agents
Reactive Oxygen Species/metabolism
Disease Models, Animal
Organometallic Compounds/toxicity
Maze Learning/drug effects
Aluminum Compounds/toxicity
Pyrones

@article {pmid42851935,
year = {2026},
author = {Ghaderi, S and Pirozzi, MA and Sharbafshaaer, M and Trojsi, F and Mohammadi, S and Fereshtehnejad, SM},
title = {Thalamic quantitative susceptibility mapping and susceptibility source separation: a critical narrative review of evidence and interpretation.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1878540},
pmid = {42851935},
issn = {1664-2295},
mesh = {Humans ; *Thalamus/diagnostic imaging/pathology ; *Magnetic Resonance Imaging/methods ; Animals ; *Brain Mapping/methods ; },
abstract = {Quantitative susceptibility mapping (QSM) measures net tissue magnetic susceptibility, which can conceal coexisting contributions of opposite sign. This is relevant to the thalamus, where nuclei differ in cellular composition, myelinated fibers, and susceptibility contrast. This narrative review evaluates what QSM and magnetic susceptibility source separation, including χ-separation, currently establish about thalamic alterations in aging and neurological disease. The synthesis prioritizes human thalamic evidence and distinguishes it from methodological validation, findings outside the thalamus, and animal experiments. We use paramagnetic component susceptibility (PCS) and diamagnetic component susceptibility (DCS) as the principal notation, with PCS nonnegative and DCS nonpositive. These model-derived components describe magnetic behavior and do not independently identify iron, myelin, calcium, amyloid, or tau. Reduced thalamic bulk susceptibility is repeatedly reported in multiple sclerosis, whereas findings in Alzheimer's disease and Parkinson's disease are less consistent. Differences in acquisition, referencing, segmentation, cohort composition, and treatment of atrophy affect interpretation, although methodological variability does not explain every disagreement. Source separation can provide information concealed by net susceptibility, but depends on relaxation modeling, acquisition conditions, and reconstruction assumptions. Evidence for thalamic protein mapping, calcification of characterization, and treatment monitoring remains limited or indirect. PCS and DCS are research measurements with potential biological interpretability; standardized acquisition and processing, independent tissue validation, longitudinal replication, and clinically useful decision thresholds are required before they can be regarded as validated clinical biomarkers.},
}

Humans
*Thalamus/diagnostic imaging/pathology
*Magnetic Resonance Imaging/methods
Animals
*Brain Mapping/methods

@article {pmid42852183,
year = {2026},
author = {Taylor, JL and Hernandez, B and Lazzeroni, LC and McNerney, MW and Heath, A and Ashford, JW and Cheng, JJ and Chao, S and Bhatt, P and Iv, M and Mojabi, FS and Yesavage, JA},
title = {Parietal and prefrontal transcranial magnetic stimulation (TMS) for mild cognitive impairment (MCI): A pilot randomized clinical trial.},
journal = {Brain disorders (Amsterdam, Netherlands)},
volume = {23},
number = {},
pages = {100322},
pmid = {42852183},
issn = {2666-4593},
support = {IK2 BX004105/BX/BLRD VA/United States ; R01 AG055526/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Even though studies of repetitive transcranial magnetic stimulation (rTMS) have demonstrated improvements in cognitive function, we know little about what site of stimulation would be ideal for improving memory.

METHODS: We investigated two sites: (1) the dorsolateral prefrontal cortex (DLPFC); and (2) the lateral parietal cortex (LPC), a more novel site. Forty amnestic MCI participants were randomized to one of three rTMS groups: (1) active DLPFC; (2) active LPC; and (3) sham. After completing 20 sessions of MRI-neuronavigated, bilateral rTMS, the participants were followed for 6 months. The primary outcome/endpoint was the California Verbal Learning Test-II (CVLT-II) list learning score assessed at 1-week post intervention.

RESULTS: Thirty-seven of 40 randomized participants provided primary endpoint data. Compared with the sham group, the active LPC group performed significantly higher on CVLT-II list learning (p = .048; standardized mean difference (SMD) = 0.86). No significant differences in CVLT-II list learning were detected between the active DLPFC and sham groups (p = .629; SMD = 0.20). Exploratory analyses revealed that the active LPC group performed better than sham on CVLT-II long-delay recall at the 1-week-post primary endpoint (p = .004; SMD = 1.30), and higher on CVLT-II semantic clustering at the 3-month follow-up (p = .015, SMD = 1.16).

CONCLUSION: The parietal cortex is a promising TMS target for improving memory function in MCI. More definitive trials are needed to compare the efficacy of parietal and DLPFC TMS for treatment of memory and cognitive impairment.},
}

@article {pmid42853103,
year = {2026},
author = {Gómez-Oliva, R and Chamorro-Francisco, A and Atienza-Navarro, I and Carrascal, L and Freire-Aragón, MD and Hernández-Galán, R and Nunez-Abades, P and García-Alloza, M and Castro, C},
title = {Sex-Specific Neurogenic and Cognitive Responses in a Murine Model of Accelerated Aging.},
journal = {Aging cell},
volume = {25},
number = {10},
pages = {e70663},
pmid = {42853103},
issn = {1474-9726},
support = {PID2022-142418OB-C21//MICIU/AEI/10.13039/501100011033 ERDF/UE/ ; PID2022-142418OB-C22//MICIU/AEI/10.13039/501100011033 ERDF/UE/ ; FEDER-UCA-2024-A2-13//Andalusia 2021-2027 ERDF/UE Operational Program/ ; },
mesh = {Animals ; Male ; *Neurogenesis/drug effects ; *Aging ; Mice ; *Cognition/drug effects/physiology ; Female ; Disease Models, Animal ; Hippocampus/drug effects ; Sex Characteristics ; },
abstract = {Aging is associated with cognitive deterioration accompanied by a reduction in hippocampal neurogenesis. Murine models have been widely used to study aging and age-related cognitive decline, as they recapitulate many of the key features of the degenerative process. Among these, the SAMP8 strain represents a well-established model of accelerated aging, characterized by early-onset and progressive cognitive impairment, Alzheimer's disease-like neuropathology, and an initial increase in hippocampal neurogenesis that ultimately depletes the neural stem cell pool. Notably, most studies using murine models of aging or neurodegeneration have focused on males or mixed-sex cohorts, leaving sex-specific differences in neurogenesis and cognitive decline largely unexplored. Recent evidence indicates that diterpenoid treatment is associated with improved cognitive performance and enhanced neurogenesis in 6-month-old male SAMP8 mice. However, whether females exhibit similar responses remains unknown. In this study, we characterized sex differences in hippocampal neurogenesis in 6-month-old SAMP8 mice and examined potential sex-dependent effects of diterpenoid therapy. Our findings reveal sex-specific differences in physiological and pathological hippocampal neurogenesis and in responsiveness to ER272 treatment. Male SAMR1 mice displayed higher baseline neurogenesis than females, while male and female SAMP8 mice followed distinct neurogenic aging trajectories. ER272 was associated with improved cognitive performance and preservation of multiple neurogenic parameters in males but showed limited effects in females. These results suggest sex-specific mechanisms of brain aging and indicate that mixed-sex analyses may mask biologically relevant differences, highlighting the importance of considering sex in aging studies and therapeutic development.},
}

Animals
Male
*Neurogenesis/drug effects
*Aging
Mice
*Cognition/drug effects/physiology
Female
Disease Models, Animal
Hippocampus/drug effects
Sex Characteristics

@article {pmid42853296,
year = {2026},
author = {Zhao, J and Bai, Y and Wang, C and Guo, P and Wang, Z and Du, G and Liu, A},
title = {Fraxetin Ameliorates Cognitive Impairment in STZ-Induced Mice: Involvement of Suppressed Microglial Hyperactivation and Improved Mitochondrial Dysfunction.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {},
pmid = {42853296},
issn = {1557-1904},
support = {2025177//Tianjin Municipal Research Project on Integrated Traditional Chinese and Western Medicine/ ; 2021-I2M-1-028//CAMS Innovation Fund for Medical Sciences/ ; 82574701//National Natural Science Foundation of China/ ; },
mesh = {Animals ; Mice ; *Microglia/drug effects/metabolism ; *Mitochondria/drug effects/metabolism ; *Streptozocin/toxicity ; Male ; *Cognitive Dysfunction/chemically induced/drug therapy/metabolism ; *Coumarins/pharmacology/therapeutic use ; Mice, Inbred C57BL ; },
abstract = {Therapeutic for Alzheimer's disease (AD) remains a pressing medical challenge in the field of neuroscience. Natural compounds with structural diversity and multi-target regulatory properties have attracted increasing attention for the treatment of complex neurodegenerative disorders. ‌Fraxetin, previously identified through computer-aided virtual screening, C. elegans assays, and in vitro cellular models as a potential anti-AD natural compound, was further investigated in this study using established in vivo and in vitro systems to evaluate its efficacy in ameliorating cognitive function and elucidate underlying mechanisms. A sporadic AD mouse model was established by intracerebroventricular injection of STZ (3 mg/kg). Fraxetin (3, 10, and 30 mg/kg/day, po.) was administered until the mouse sacrifices. Cognitive performance was evaluated using the novel object recognition, passive avoidance, and Morris water maze tests. STZ induced cerebral energy metabolism disturbances accompanied by mitochondrial dysfunction, neuroinflammation, oxidative stress, neuronal and synaptic loss, and cholinergic system impairment. ‌Behavioral tests confirmed that fraxetin ameliorated cognitive deficits in STZ-induced mice. Further studies revealed that fraxetin preserved mitochondrial structural integrity and enhanced mitochondrial biogenesis, accompanied by upregulation of the Sirt1/PGC-1α/Nrf1/TFAM pathway. In parallel, fraxetin attenuated microglial overactivation and neuroinflammatory responses. Consistently, in LPS-stimulated BV2 microglial cells, fraxetin inhibited nitric oxide and inflammatory mediator release, which was associated with modulation of the TLR2/MYD88/NF-κB signaling pathway, while restoring cellular bioenergetic status, indicating coordinated regulation of inflammation-associated metabolic dysfunction. Importantly, fraxetin attenuated neurodegenerative alterations in STZ-treated mice, as evidenced by reduced neuronal loss and synaptic degeneration. These effects were associated with activation of the BDNF/TrkB/ERK/CREB neurotrophic pathway and inhibition of acetylcholinesterase activity, supporting preservation of synaptic and cholinergic function. This study provides experimental evidence supporting fraxetin as a promising natural multi-target candidate for the intervention of AD.},
}

Animals
Mice
*Microglia/drug effects/metabolism
*Mitochondria/drug effects/metabolism
*Streptozocin/toxicity
Male
*Cognitive Dysfunction/chemically induced/drug therapy/metabolism
*Coumarins/pharmacology/therapeutic use
Mice, Inbred C57BL

@article {pmid42855152,
year = {2026},
author = {Gerson, G and Nogueira, GN and Teixeira, MJ},
title = {Plasma p-tau217 as a biomarker for Alzheimer's disease: diagnostic and prognostic value in clinical and population-based studies.},
journal = {Arquivos de neuro-psiquiatria},
volume = {84},
number = {10},
pages = {1-8},
pmid = {42855152},
issn = {1678-4227},
mesh = {Humans ; *Alzheimer Disease/diagnosis/blood ; Biomarkers/blood ; *tau Proteins/blood ; Prognosis ; Predictive Value of Tests ; Sensitivity and Specificity ; Phosphorylation ; Reproducibility of Results ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia worldwide, and blood-based biomarkers are emerging as accessible diagnostic tools. Plasma phosphorylated tau at position 217 (p-tau217) has shown promise in early detection.

OBJECTIVE: To evaluate the diagnostic accuracy, prognostic value, and applicability of plasma p-tau217 in AD compared with other biomarkers.

METHODS: We conducted an integrative review on the PubMed, Scopus, Embase, and Cochrane Library databases (2018-2024). Eligible observational and diagnostic studies assessing p-tau217 in plasma were included. Study selection and quality assessment followed the Standards for Reporting of Diagnostic Accuracy (STARD) and Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.

RESULTS: We analized 9 studies involving more than 6 thousand participants analyzed. Plasma p-tau217 demonstrated high accuracy (area under the curve [AUC]: 0.86-0.94) for detecting tau and amyloid pathology, outperforming p-tau181. It was effective in diverse populations, asymptomatic individuals, and primary care settings. Longitudinal data suggest predictive value for cognitive decline.

CONCLUSION: Plasma p-tau217 is a reliable and non-invasive biomarker for AD, with applications in diagnosis, prognosis, and treatment monitoring. Standardization and multicenter validation are necessary before clinical implementation.},
}

Humans
*Alzheimer Disease/diagnosis/blood
Biomarkers/blood
*tau Proteins/blood
Prognosis
Predictive Value of Tests
Sensitivity and Specificity
Phosphorylation
Reproducibility of Results

@article {pmid42855813,
year = {2026},
author = {Alten, B and Gokcal, E and Sperling, RA and Shirzadi, Z and Chhatwal, JP and Gurol, ME and Kasner, SE and Greenberg, SM and Cucchiara, BL},
title = {Centrum Semiovale Perivascular Spaces Predict First Hemorrhagic Lesion in Asymptomatic Amyloid-Positive Individuals.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78388},
pmid = {42855813},
issn = {1531-8249},
abstract = {OBJECTIVE: Identification of cerebral amyloid angiopathy (CAA) before its hemorrhagic manifestations remains limited. We aimed to determine whether severe enlarged perivascular spaces in the centrum semiovale (EPVS-CSO) identify a prehemorrhagic stage of sporadic CAA by predicting the first appearance of CAA-related hemorrhagic lesions or incident cognitive decline in amyloid-positive, cognitively unimpaired, hemorrhage-free older adults.

METHODS: We performed a secondary analysis of the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial, a phase 3 randomized study in cognitively unimpaired, amyloid-positive older adults. Participants with baseline hemorrhagic lesions were excluded. Baseline EPVS-CSO severity was dichotomized as severe versus nonsevere. Severe basal ganglia EPVS, more closely associated with hypertensive small vessel disease, was evaluated as a topographical negative-control exposure. The primary outcome was incident strictly lobar cerebral microbleeds or cortical superficial siderosis. The secondary outcome was longitudinal cognitive trajectories measured by the Preclinical Alzheimer Cognitive Composite.

RESULTS: Among 932 participants (mean age 71.7 ± 4.8 years; 61.3% female), 101 (10.8%) had severe EPVS-CSO at baseline. Over a median follow up of 5.1 years (IQR 3.3-5.5 years), 33.7% of those with severe EPVS-CSO developed incident CAA-related hemorrhagic lesions compared with 13.6% of those with nonsevere EPVS-CSO (adjusted HR 2.85, 95% CI 1.91-4.25; p < 0.0001). Severe basal ganglia EPVS was not associated with incident hemorrhagic lesions (adjusted HR 0.87, 95% CI 0.35-2.18; p = 0.77). Severe EPVS-CSO was not associated with early cognitive differences, and participants who developed incident hemorrhagic lesions showed more pronounced cognitive decline.

INTERPRETATION: These findings identify severe EPVS-CSO as a strong predictor of first appearance of CAA-related hemorrhagic lesions in amyloid-positive individuals, supporting integration of amyloid biomarkers into magnetic resonance imaging-based Boston criteria. Identifying markers of the transition of CAA from a nonhemorrhagic to a hemorrhagic stage provides a potential foundation for approaching primary prevention of CAA-related hemorrhage. ANN NEUROL 2026.},
}

@article {pmid42845560,
year = {2026},
author = {Taylor, JP and Alam, JJ and Gomperts, SN and Honig, LS and Prins, ND and Koubiyr, I and Chu, HM and Gardner, A and Blackburn, K and Schoonheim, MM and Teunissen, CE and Galvin, JE},
title = {A Phase 2b randomized clinical trial of the oral p38α inhibitor neflamapimod in dementia with Lewy bodies (DLB).},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10623740/v1},
pmid = {42845560},
issn = {2693-5015},
abstract = {Background: There is high unmet need in dementia with Lewy bodies (DLB). Neflamapimod, showed clinical activity against cognitive and motor endpoints at a dose of 40mg three-times-daily (TID) in a prior phase 2a study in DLB, most prominently in those without Alzheimer disease (AD) co-pathology, assessed by plasma ptau181. Methods: 16-week randomized, placebo-controlled clinical trial, with a 32-week open label extension, conducted at 43 centers in the US, UK and Netherlands. 159 participants with probable DLB by consensus criteria, screened to enrich for patients without AD co-pathology (plasma ptau181≥27.2 pg/mL excluded), randomized between August 2023 and June 2024 to neflamapimod 40mg (80 participants) or matching placebo (79 participants) capsules, TID. Mean age 71.4 (6.1), 85.6% male. Primary outcome measure: change in Clinical Dementia Rating Sum-of-Boxes (CDR-SB). Secondary outcome measures: Timed up and Go test, ADCS Clinical Global Impression of Change, and a study-specific cognitive test battery. Biomarker measures: plasma levels of glial fibrillary acidic protein and neurofilament light chain, and basal forebrain atrophy by structural MRI (sub-study in 18 participants). Results: There was no significant difference between neflamapimod and placebo on the primary outcome measure, change in CDR-SB. There were also no differences seen on secondary clinical outcome measures and the two plasma biomarkers, though in the sub-study, improvement relative to placebo was seen with neflamapimod on change in right basal forebrain volume from baseline to week 16. In exploratory analyses, the treatment group difference in change in CDR-SB favored neflamapimod compared to placebo among participants with low (<21 pg/mL) screening plasma p-tau181. Pharmacokinetic data showed that mean trough neflamapimod plasma drug-concentrations (C trough) were lower than expected, and treatment effect favoring neflamapimod was seen in participants with C trough above the study median. Discontinuation due to adverse events was 2.5% (2 of 79) with neflamapimod and 1.3% (1 of 80) with placebo Discussion: The phase 2a clinical study findings were not replicated, potentially due to the inclusion of a higher proportion of patients with AD co-pathology than targeted and the use of neflamapimod drug product that did not achieve expected plasma drug concentrations. Registered at clinicaltrials.gov on 17 May 2023 (NCT0586966).},
}

@article {pmid42841964,
year = {2026},
author = {Jellinger, KA},
title = {Depression and anxiety in vascular dementia: an update.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {42841964},
issn = {1435-1463},
abstract = {Depression with a prevalence between 20% and 86% and anxiety with a prevalence up to 72% most frequently coexist with vascular dementia (VaD) and reciprocally increase disease risks. Both psychopathological disorders are usually more frequent and more severe in patients with VaD than in those with Alzheimer disease (AD). Although there is a significant association between depression and all-cause dementia, VaD with depression has more comorbidities and higher mortality than without depression. A history of depression prior to dementia is more common than in AD, while its pre-disease state is a matter of discussion. Although the diagnosis of depression related to cerebrovascular disorders is based on the criteria of DSM-V, VaD/depression has been suggested to be a distinct subtype differing from late-life depression and major depressive disorder, whereas others reported broadly similar depressive symptom profiles across VaD, AD, and AD plus VaD. Depression in the course of VaD, which is frequently underdiagnosed and undertreated, has been related to a variety of pathogenic mechanisms, in particular cerebral small vessel disease (CSVD), cerebral white matter lesions, damage to fronto-subcortical brain circuits, neuroinflammation, impaired neurotrophic support, and imbalance of neurotransmitter/kynurenine pathways. Multimarkers, like high CSVD and white matter hyperintensity burden, the presence of visible perivascular spaces, inflammatory markers, neurofilament light chain levels, and other biomarkers may support clinical diagnosis of VaD/depression. Treatment planning should consider a modest response to antidepressants, while treatment of vascular and metabolic comorbidities may provide promising targets for its prevention and treatment. Electroconvulsive therapy and transcranial direct current stimulation as augmentation treatment of an adequate pharmacotherapy are potential strategies in the management of VaD/depression that is known to be often unresponsive to antidepressants only. However, their effectiveness needs further investigation to assess which interventions are appropriate and effective in clinical practice.},
}

@article {pmid42841989,
year = {2026},
author = {Kim, H and Hwang, E and Kim, SJ},
title = {The calcium channel blocker diltiazem ameliorates parthanatos in juvenile neuronal ceroid lipofuscinosis.},
journal = {Journal of molecular medicine (Berlin, Germany)},
volume = {104},
number = {1},
pages = {},
pmid = {42841989},
issn = {1432-1440},
support = {2021R1F1A1049562//Ministry of Education/ ; 2021374C10-2123-BD02//Korea Forestry Promotion Institute/ ; },
mesh = {*Diltiazem/pharmacology/therapeutic use ; *Neuronal Ceroid-Lipofuscinoses/drug therapy/metabolism/pathology/genetics ; Humans ; *Calcium Channel Blockers/pharmacology/therapeutic use ; *Parthanatos/drug effects ; Poly (ADP-Ribose) Polymerase-1/metabolism ; Poly Adenosine Diphosphate Ribose/metabolism ; Calcium/metabolism ; },
abstract = {Accumulation of pre-mutagenic 8-oxoguanine and impaired DNA repair can lead to poly(ADP-ribose) (PAR) accumulation and parthanatos in Alzheimer's disease, the leading cause of age-dependent dementia. However, the occurrence of parthanatos has not been well established in other types of dementia, including juvenile neuronal ceroid lipofuscinosis (JNCL), a major form of juvenile dementia. In this study, we investigated parthanatos-associated pathology in JNCL using patient-derived lymphoblasts (PDLs). Quantitative immunofluorescence microscopy revealed increased accumulation of 8-oxoguanine and PAR in JNCL-PDLs. JNCL is known to exhibit elevated intracellular calcium, which activates PAR polymerase - 1 (PARP1). The L-type calcium channel blocker diltiazem effectively suppressed PAR accumulation in JNCL-PDLs, even under co-treatment with a calcium ionophore. Diltiazem also reduced 8-oxoG accumulation in JNCL-PDLs, although this effect was largely calcium independent. Subcellular fractionation followed by immunoblotting showed that diltiazem enhanced nuclear recruitment of OGG1 and its partner proteins. These protective effects were abolished by OGG1 knockdown, suggesting a dual role of diltiazem in regulating both calcium signaling and OGG1 activity. Collectively, our data identify that parthanatos as novel therapeutic target for JNCL and propose diltiazem as a potential therapeutic agent. KEY MESSAGES: Increased poly(ADP-ribose) accumulation represents a novel therapeutic target in juvenile neuronal ceroid lipofuscinosis caused by CLN3 mutations. Increased PARP1 expression and decreased PARP1 cleavage lead to elevated poly(ADP-ribose) accumulation in juvenile neuronal ceroid lipofuscinosis. Diltiazem ameliorates poly(ADP-ribose) accumulation in patient-derived cell models of juvenile neuronal ceroid lipofuscinosis by suppressing PARP1 expression and 8-oxoguanine accumulation.},
}

*Diltiazem/pharmacology/therapeutic use
*Neuronal Ceroid-Lipofuscinoses/drug therapy/metabolism/pathology/genetics
Humans
*Calcium Channel Blockers/pharmacology/therapeutic use
*Parthanatos/drug effects
Poly (ADP-Ribose) Polymerase-1/metabolism
Poly Adenosine Diphosphate Ribose/metabolism
Calcium/metabolism

@article {pmid42842169,
year = {2026},
author = {Singh, RK and Banerjee, C and Mehan, S},
title = {Beyond Histamine Blockade: Clemastine Fumarate as a Promoter of Myelin Regeneration, Inflammatory Regulation, and Neuroimmune Modulation in CNS Disorders.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {},
pmid = {42842169},
issn = {1557-1904},
mesh = {Animals ; Humans ; *Clemastine/pharmacology/therapeutic use ; *Central Nervous System Diseases/drug therapy/immunology/metabolism ; *Myelin Sheath/drug effects ; *Neuroimmunomodulation/drug effects/physiology ; *Remyelination/drug effects/physiology ; Neuroinflammatory Diseases/drug therapy/immunology ; *Histamine H1 Antagonists/pharmacology/therapeutic use ; },
abstract = {Clemastine fumarate, a first-generation H1 antihistamine, has emerged as a promising candidate for drug repurposing in neurodegenerative and neuropsychiatric disorders owing to its ability to cross the blood-brain barrier and interact with multiple central nervous system targets. Experimental studies indicate that clemastine promotes remyelination by stimulating the differentiation of oligodendrocyte precursor cells into mature, myelin-producing oligodendrocytes, thereby restoring myelin integrity and improving axonal function in experimental models. In addition to its remyelinating properties, preclinical evidence suggests that clemastine may attenuate neuroinflammation by modulating microglial activation and suppressing pro-inflammatory signalling pathways. These effects have been associated with improved structural and functional outcomes in experimental models of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury, stroke, and several neuropsychiatric disorders. Mechanistically, clemastine primarily acts through muscarinic M1 receptor antagonism to promotes remyelination, while additional pathways including PI3K/Akt, ERK1/2, autophagy-related signalling, inflammasome modulation, and sigma-1 receptor signalling have been proposed based on experimental evidence but remain incompletely understood and require further mechanistic validation. Among the neurological disorders investigated multiple sclerosis currently has the strongest clinical evidence with early clinical trials demonstrating modest remyelinating activity. In contrast, evidence supporting the use of clemastine in other neurological disorders remains largely confined to preclinical studies. Several translational challenges also remain unresolved including dose optimisation, treatment timing, long-term safety, sedative and anticholinergic adverse effects, and patient selection. Future research should focus on refining pharmacokinetic properties, optimising dosing strategies, evaluating rational combination therapies, and identifying predictive biomarkers to facilitate clinical translation. Although current evidence highlights the therapeutic potential of clemastine fumarate, its application beyond multiple sclerosis remains investigational and will require rigorous mechanistic studies together with well-designed clinical trials before broader clinical use can be established.},
}

Animals
Humans
*Clemastine/pharmacology/therapeutic use
*Central Nervous System Diseases/drug therapy/immunology/metabolism
*Myelin Sheath/drug effects
*Neuroimmunomodulation/drug effects/physiology
*Remyelination/drug effects/physiology
Neuroinflammatory Diseases/drug therapy/immunology
*Histamine H1 Antagonists/pharmacology/therapeutic use

@article {pmid42842469,
year = {2026},
author = {Mah, E and Gallagher, D and Kang, Y and Gao, F and Ramirez, J and Ismail, Z and Black, SE and Cao, X and Herrmann, N and Marzolini, S and Oh, P and Chen, JJ and Survilla, K and Swardfager, W and Vieira, D and Rapoport, MJ and Lanctôt, KL},
title = {White matter hyperintensities moderate neuropsychiatric response to N-acetylcysteine and exercise therapy in vascular mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261490542},
doi = {10.1177/13872877261490542},
pmid = {42842469},
issn = {1875-8908},
abstract = {BackgroundVascular mild cognitive impairment (vaMCI) is frequently accompanied by neuropsychiatric symptoms (NPS), particularly apathy, which are associated with white matter hyperintensities (WMH). N-acetylcysteine (NAC) combined with exercise may provide neuroprotective benefits.ObjectiveWe hypothesized that baseline frontal and global WMH burden would moderate the neuropsychiatric response to NAC plus exercise. We further hypothesized that the strongest domain-specific effects would be observed for apathy and affective dysregulation.MethodsParticipants with vaMCI were randomized to NAC (2400 mg daily) or placebo plus exercise for 6 months. WMH volumes were quantified using structural MRI. NPS were assessed using the Mild Behavioral Impairment Checklist (MBI-C) at baseline, 3 months, and 6 months. Negative binomial generalized linear mixed models examined WMH × time × treatment interactions. False discovery rate (FDR) correction was applied.ResultsFifty-one participants were included. Lower baseline frontal (β = 0.229, SE = 0.070, FDR-adjusted p = 0.007) and global (β = 0.258, SE = 0.080, FDR-adjusted p = 0.007) WMH volume was associated with greater reductions in NPS over 6 months in the NAC plus exercise group. This effect was driven by improvements in apathy (frontal: β = 0.186, SE = 0.076, FDR-adjusted p = 0.048; global: β = 0.207, SE = 0.089, FDR-adjusted p = 0.049).ConclusionsBaseline WMH burden moderates neuropsychiatric treatment response in vaMCI. These findings support the importance of optimizing care for cerebrovascular risk factors in this vulnerable population.},
}

@article {pmid42843100,
year = {2026},
author = {Zhu, Y and Jafari, Z and Kolb, BE and Mohajerani, MH},
title = {From pathogenesis to non-medical therapy: A review of exploring sensory and multi-sensory stimulation as a non-invasive treatment approach for Alzheimer's disease.},
journal = {Neuroscience and biobehavioral reviews},
volume = {191},
number = {},
pages = {107004},
doi = {10.1016/j.neubiorev.2026.107004},
pmid = {42843100},
issn = {1873-7528},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder, marked by the accumulation of amyloid-beta plaques, tau pathology, and synaptic dysfunction, ultimately leading to memory loss, cognitive decline, neuropsychiatric symptoms and neuronal degeneration that impairs daily functioning. Despite the availability of pharmacological treatments developed to slow down symptom progression, their clinical efficacy remains uncertain, and they are frequently associated with adverse side effects, underscoring the urgent demand for safer and more effective therapeutic alternatives. Non-pharmacological approaches, therefore, have been investigated and are considered promising alternative therapeutic strategies for AD. This paper outlines the pathological features and neural network changes that occur across the progression of Alzheimer's disease (AD), reviews the effects of different sensory stimulation approaches on reducing these AD-associated changes, and discusses the potential mechanisms underlying various sensory and multisensory stimulation interventions in mitigating AD-related symptoms. These sensory stimulation interventions, including 40 Hz Gamma Entrainment Using Sensory Stimulation [GENUS], Photobiomodulation, Bright Light Therapy, Music Therapy, Aromatherapy, Tactile Stimulation, and Multisensory Stimulation, are found to slow down the progression of AD by ameliorating multiple AD pathologies, enhancing cognitive function, promoting neuroplasticity, regulating sleep patterns, and reducing behavioural or neuropsychiatric symptoms. Crucially, this present work integrates both human and animal studies, aligning clinical outcomes with mechanistic insights derived from animal studies, thereby bridging preclinical and clinical research to promote the translation of sensory interventions into effective treatments for patients with AD.},
}

@article {pmid42843827,
year = {2026},
author = {Hall, J},
title = {Lessons from the history of antipsychotic discovery: part 3 - muscarinic mechanisms.},
journal = {BJPsych bulletin},
volume = {},
number = {},
pages = {1-4},
doi = {10.1192/bjb.2026.10267},
pmid = {42843827},
issn = {2056-4694},
abstract = {After more than seven decades in which antipsychotic drug development has been dominated by dopaminergic mechanisms, the recent emergence of a muscarinic receptor-based treatment represents a conceptual shift in the pharmacotherapy of psychosis. This article reviews the history and development of the first clinically effective non-dopaminergic antipsychotic, tracing its origins to unexpected behavioural effects observed during trials of muscarinic agonists developed for Alzheimer's disease. Early studies of the muscarinic agonist xanomeline demonstrated antipsychotic efficacy, but were limited by poor tolerability due to peripheral cholinergic adverse effects. Subsequent progress depended on the dissociation of central therapeutic effects from peripheral side-effects, through the combination of xanomeline with the peripherally restricted muscarinic antagonist trospium. The development of this treatment highlights several broader lessons for psychiatric drug discovery, including the value of revisiting previously abandoned compounds, the benefits of leveraging existing human safety data on the importance of early-phase translational research and the role of innovative companies.},
}

@article {pmid42844308,
year = {2026},
author = {Gandhi, SM and Patel, S and Haswani, NG and Wahab, S and Sabah, ZU and Kapoor, DU},
title = {RVG29-functionalized nanocarriers for brain-targeted therapy of neurodegenerative diseases: mechanisms, therapeutic advances, and translational perspectives.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42844308},
issn = {1432-1912},
abstract = {Neurodegenerative diseases (NDs) affect more than 55 million people worldwide, with this number projected to exceed 139 million by 2050 due to population aging. Alzheimer's disease (AD) accounts for 60-70% of dementia cases, while Parkinson's disease (PD) affects over 10 million individuals globally, highlighting the growing clinical and socioeconomic burden of these progressive neurological disorders. Effective treatment of AD, PD, amyotrophic lateral sclerosis (ALS), and related central nervous system disorders remains hindered by the blood-brain barrier (BBB), poor brain accumulation, rapid systemic clearance, and off-target toxicity. RVG29, a 29-amino-acid peptide derived from rabies virus glycoprotein, has emerged as a promising brain-targeting ligand because of its high affinity for nicotinic acetylcholine receptors expressed on neuronal and brain endothelial cells. This review critically examines the mechanisms underlying RVG29-mediated receptor-dependent BBB transcytosis, intracellular trafficking, and neuronal uptake. Furthermore, it comprehensively evaluates RVG29-functionalized lipid nanoparticles, polymeric nanoparticles, exosomes, biomimetic nanocarriers, micelles, inorganic nanostructures, and hybrid systems with respect to their physicochemical characteristics, targeting efficiency, therapeutic efficacy, and safety. Collectively, these nanocarriers demonstrate enhanced BBB penetration, increased drug accumulation in diseased brain regions, and efficient delivery of small molecules, genes, mRNA, and siRNA. By modulating oxidative stress, neuroinflammation, protein aggregation, ferroptosis, and mitochondrial dysfunction, RVG29-engineered nanocarriers provide significant neuroprotection with favorable biocompatibility and minimal immunogenicity. Despite these advances, challenges related to large-scale manufacturing, peptide stability, regulatory approval, and long-term biosafety must be addressed to facilitate their clinical translation as precision neurotherapeutics.},
}

@article {pmid42837878,
year = {2026},
author = {Mohan, R and Mali, S and Ilango, P and Jainulabdeen, J},
title = {Gather-excite attention-driven deep learning model for Alzheimer disease detection from MRIs using adaptive residual-DenseNet strategy.},
journal = {Psychiatry research. Neuroimaging},
volume = {364},
number = {},
pages = {112344},
doi = {10.1016/j.pscychresns.2026.112344},
pmid = {42837878},
issn = {1872-7506},
abstract = {In worldwide, Alzheimer's Disease (AD) is one of the leading cause of death and requires earlier diagnosis for timely and effective treatment management. Neuroimaging, particularly Magnetic Resonance Imaging (MRI) provides a promising solution to detect the AD at earlier stages. Timely detection of variations in brain is critical for enabling effective interventions and mitigating the progression of AD. However, manual analysis of MRI scans remains challenging and time-consuming due to structural complexity and variations across individuals. Subtle patterns and background noise often remain undetected with conventional methods, thereby limiting diagnostic accuracy. Computer-based techniques improve reliability, but MRI heterogeneity complicates feature extraction and prediction model development. To overcome the issues of conventional models, the research study proposes Gather-Excite Adaptive Residual-Densenet (GE-ARDNet) model for AD detection. Here, the MRI images are collected and progressed through GE-ARDNet that integrates the residual learning with dense connectivity to enhance feature propagation. The Gather-Excite model exploits contextual information using an attention strategy, focusing on discriminative regions associated with AD pathology. Model efficiency is improved by optimizing Residual-Densenet parameters with Renovated Parameter Masterpiece Optimizer (RPMO), ensuring robust feature learning and generalization. Finally, the cross-validation and independent analysis is validated, demonstrating its effectiveness of the proposed model.},
}

@article {pmid42838180,
year = {2026},
author = {Elfiky, AM and Shahy, EM and Mahmoud, AA},
title = {Probiotics Attenuate AlCl3-Induced Alzheimer's Disease via Gut-Brain Axis Modulation and Suppression of NF-κB/NLRP3 Neuroinflammation.},
journal = {Physiology & behavior},
volume = {},
number = {},
pages = {115532},
doi = {10.1016/j.physbeh.2026.115532},
pmid = {42838180},
issn = {1873-507X},
abstract = {Disruptions along the brain-gut-microbiota axis significantly contribute to Alzheimer's disease (AD) pathogenesis. This study evaluated the therapeutic potential of a multi-strain probiotic mixture in mitigating cognitive decline, neuroinflammation, and amyloid pathology in an AD rat model. In the present study, after induction of AD in rats by oral administration of AlCl3 (50 mg/kg) for 28 days, followed by oral treatment with a probiotic mixture (10[9] log CFU/ml) for 42 days. Behavioral assessments were conducted during the final week. Hippocampal tissues were obtained for histopathological and gene expression analyses and fecal samples were subjected to full-length 16S rRNA gene sequencing via Oxford Nanopore approach. Probiotics significantly improved AD-induced deficits in locomotor activity, exploratory behavior, and spatial recognition memory. Histological analysis revealed marked reductions in hippocampal β-amyloid deposition and substantial restoration of colonic mucosal barrier integrity. Microbiota profiling showed that probiotics reversed dysbiosis, significantly enriching beneficial genera (Blautia, Clostridium, Eubacterium). Blautia abundance was strongly negatively correlated with NF-κB expression. Mechanistically, probiotics suppressed neuroinflammation by down-regulating pro-inflammatory cascades TNF-α, NLRP3, IL-1β, and NF-κB activation. Furthermore, treatment suppressed amyloidogenic processing via decreased APP mRNA and enhanced Aβ clearance through upregulation of LRP1 and modulation of AGER. These findings provide integrative evidence that probiotics exert neuroprotective and immunomodulatory effects, supporting their translational potential as a preventive strategy against AD-related cognitive decline.},
}

@article {pmid42838381,
year = {2026},
author = {Rana, A and Mélanie, P and Van Amanda, L and Nathalie, BH},
title = {"Structural and Metabolic Reprogramming by Docosahexaenoic Acid in Neuronal Cell Models of Alzheimer's Disease".},
journal = {Biochimie},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.biochi.2026.10.005},
pmid = {42838381},
issn = {1638-6183},
abstract = {Docosahexaenoic acid (DHA; 22:6n-3) is the most abundant omega-3 polyunsaturated fatty acid in the mammalian brain and an essential structural component of neuronal membranes. Several research studies indicate that DHA plays critical roles in maintaining membrane lipid composition, synaptic integrity, mitochondrial function, and metabolic homeostasis, processes that are disrupted in Alzheimer's disease (AD) and other neurodegenerative disorders. Because brain DHA availability depends largely on systemic metabolism and liver-brain communication, alterations in DHA homeostasis have been proposed as contributing factors to AD pathogenesis. In vitro neuronal culture models have been pivotal in investigating the molecular and biochemical mechanisms underlying DHA-mediated neuroprotection under disease-related conditions. This mini review summarizes how DHA treatment modulates cellular membrane organisation, synaptogenesis and cytoskeletal integrity, and its neuroprotective role in in vitro neuronal models of AD. Collectively, the literature supports DHA as a key modulator of the structure and metabolic mechanisms at the cellular level and supports the hypothesis that its greatest benefit may occur as a preventive or early-stage intervention. Although effective therapeutic interventions are still lacking, and more investigations integrating next-generation cellular models are still needed, these models provide crucial insights for developing targeted therapeutic applications in AD.},
}

@article {pmid42838860,
year = {2026},
author = {Na, S and Kim, HS and Kim, GH and Kwon, OD and Shim, YS and Lee, CN and Rhee, HY and Choi, H and Hong, YJ and Lee, J and Moon, SY and Park, KH},
title = {Memantine in Korean Alzheimer's disease: A prospective real-world REMIND study.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100298},
doi = {10.1016/j.inpsyc.2026.100298},
pmid = {42838860},
issn = {1741-203X},
abstract = {OBJECTIVES: Prospective real-world evidence on memantine in Korean patients with Alzheimer's disease remains limited. This study evaluated its real-world effectiveness and tolerability over 24 weeks of routine clinical practice.

DESIGN & SETTING: Multicenter, prospective, single-arm observational study conducted at twelve university-affiliated tertiary hospitals in Korea.

PARTICIPANTS: Patients aged ≥ 50 years with Alzheimer's disease (Mini-Mental State Examination score of 5-20 and either a Clinical Dementia Rating of 2-3 or a Global Deterioration Scale score of 4-7) initiated on memantine (Ebixa®) 10-20 mg/day. The safety set comprised 401 patients and the effectiveness set 339.

MEASUREMENTS: The primary outcome was change in the Clinical Dementia Rating global score at Week 24. Secondary outcomes were changes in the Clinical Dementia Rating Sum of Boxes, Mini-Mental State Examination, Neuropsychiatric Inventory, and Zarit Burden Interview at Weeks 12 and 24, together with treatment persistence and adverse events.

RESULTS: At Week 24, 86.6% of 339 effectiveness-set patients remained within their baseline Clinical Dementia Rating category, 10.5% worsened, and 2.9% improved. Mini-Mental State Examination scores increased and Neuropsychiatric Inventory total scores decreased at both visits (all p < 0.05), with small standardized effect sizes (absolute d 0.08-0.17). Zarit Burden Interview scores increased at both visits. Treatment persistence was 89.5% at Week 24, and drug-related adverse events occurred in 17.7%.

CONCLUSION: Over 24 weeks of memantine treatment, most patients remained within their baseline Clinical Dementia Rating category, cognitive and neuropsychiatric scores showed small within-patient changes, caregiver burden increased, and tolerability was acceptable.},
}

@article {pmid42840164,
year = {2026},
author = {Tsai, E and Wang, Z and Truglio, J},
title = {A computational-first proof-of-concept for dual-function metal chelation and aggregate neutralization in an Aβ42 Drosophila model.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1912315},
pmid = {42840164},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) pathology is amplified by a self-reinforcing metal-Aβ-ROS axis, in which redox-active Cu and Fe bound to Aβ N-terminal histidines catalyze Fenton-like ROS generation and accelerate aggregation. Existing single-target interventions - anti-amyloid antibodies, antioxidants, metal-protein attenuating compounds, aggregation inhibitors, and photooxygenation catalysts - each address only one node of this loop. We used a computational-first framework to evaluate a dual-function strategy targeting two connected points of the axis: upstream redox-active metal sequestration by maltol, and downstream photodynamic modification of Aβ aggregates via endogenous protoporphyrin IX (PpIX), generated from 5-aminolevulinic acid (5-ALA) under 400 nm illumination. Drosophila experiments served as functional validation, testing whether this combined intervention improved Aβ42-associated behavioral and survival outcomes and was tolerated in wild-type (WT) flies. DFT calculations (B3LYP-D3BJ/def2-SVP//def2-TZVP, CPCM/SMD water) showed deprotonated maltol localizes oxygen-donor electron density comparable to deprotonated deferiprone, and forms a converged, solvent-stabilized Fe(III)-maltol complex. Cu(II) and Zn(II) coordination was weak and geometrically incomplete, indicating an Fe-preferential rather than broadly nonspecific chelation profile; the study does not demonstrate protection against Cu(II)-mediated ROS. Time-dependent DFT predicted PpIX excitations spanning the visible/near-UV range consistent with photosensitizer behavior, and docking against Aβ42 fibril 5OQV showed PpIX engaged the central hydrophobic/turn surface more strongly than chlorin e6 or maltol. In a pan-neuronal Aβ42 Drosophila model, dual treatment improved climbing performance (p = 2.39 × 10[-3] vs. untreated Aβ42) and extended lifespan (log-rank p = 6.04 × 10[-13]; median survival ∼40 d); WT + Treatment flies appeared tolerant, though no formal statistical contrast was pre-specified. Treatment-group ThT amyloid burden was not measured, so no amyloid-reduction claim is made. Because chelation-only and 5-ALA/light-only arms were not included, we cannot attribute improvement to either intervention alone and cannot make a formal claim of additive or interactive effects between the two intervention components. The combined intervention was associated with improved behavioral and survival outcomes in the Aβ42 Drosophila model. Because the present study lacks single-intervention controls and treatment-group pathological measurements, these findings do not establish the mechanism responsible for the observed functional improvement. The study illustrates how ground-state, excited-state, and docking calculations can jointly inform a computationally motivated intervention tested in a tractable organismal model.},
}

@article {pmid42840889,
year = {2026},
author = {Praveen, R and Gadaleta, A and Spada, G and Miniero, DV and Reza, A and Chaudhari, TY and Rahman, A and Catto, M and Hoda, N},
title = {Design, synthesis, and biological evaluation of naphthalimide derivatives as dual monoamine oxidase-B and amyloid-β aggregation inhibitors for Alzheimer's disease.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42840889},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disorder with multifactorial pathogenesis. Amyloid beta (Aβ) and monoamine oxidase (MAO) are among the key therapeutic targets for its treatment. In this investigation, a series of 18 new naphthalimide-based derivatives were synthesized and assessed for multitarget activity against hAChE, esBuChE, MAO-A, MAO-B, Aβ, and paired helical fragment 6 (PHF6) aggregation. The screened compounds predominantly exhibited dual inhibition of MAO-B and Aβ aggregation to counteract oxidative stress and plaque formation. Among the tested compounds, P12 and P17 were found to have remarkable inhibition against Aβ, with 83% and 91% inhibition, respectively, compared to the reference compound quercetin (75% inhibition). The compound P10 was the most effective MAO-B inhibitor, with an IC50 value of 3.09 ± 0.10 µM. Cytotoxicity studies in SH-SY5Y cells confirmed that compounds were non-toxic up to 25 µM. Additionally, the neuroprotection assays revealed that P10 was capable of reducing oxidative stress effectively against H2O2-induced toxicity, while P12 showed superior protection against Aβ-induced neurotoxicity in SH-SY5Y cells. Furthermore, in silico investigations provided structural insights into the predicted ligand-target interaction modes and dynamic behavior of the selected compounds with MAO-B and monomeric Aβ1-42. Consequently, all these findings underscore that naphthalimide derivatives are promising dual inhibitors of amyloid-β aggregation and MAO-B and have potential for further development as MTDLs for AD.},
}

@article {pmid42840967,
year = {2026},
author = {Brenner, M and Sharma, A and Wang, P},
title = {Ionizing radiation and Alzheimer's disease: epidemiology, mechanisms, and eCIRP-mediated tau pathology.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1961728},
pmid = {42840967},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/epidemiology/metabolism/etiology/pathology ; Animals ; *Radiation, Ionizing ; *RNA-Binding Proteins/metabolism ; *tau Proteins/metabolism ; },
abstract = {As human radiation exposure expands through medical imaging, nuclear industry growth, and the acceleration of crewed space exploration, understanding the molecular mechanisms linking radiation to Alzheimer's disease (AD) is becoming an increasingly urgent priority. Here, we review epidemiological, mechanistic, and therapeutic evidence for a relationship between ionizing radiation and AD, focusing on a neuroinflammatory pathway centered on extracellular cold-inducible RNA-binding protein (eCIRP). Epidemiological support comes from occupational cohorts of nuclear workers and studies linking residential radon to AD mortality; a meta-analysis of 18 studies finds an 11% increased all-cause dementia risk per 100 mSv. Mechanistically, ionizing radiation generates DNA double-strand breaks and reactive oxygen species that activate the ataxia-telangiectasia mutated (ATM) kinase and trigger rapid microglial activation, and causes the nuclear-to-cytoplasmic translocation and extracellular release of the danger-associated molecular pattern eCIRP. Released eCIRP activates neuronal cyclin-dependent kinase 5 (Cdk5), resulting in AD-like tau phosphorylation. This pathway is validated by loss-of-function studies in CIRP-knockout mice and pharmacological blockade with the eCIRP inhibitor C23. Beyond tau phosphorylation, eCIRP drives mitochondrial dysfunction and ferroptosis in myeloid cells and activates endothelial cell death pathways that may compromise blood-brain barrier integrity. eCIRP links radiation-induced neuroinflammation to tau-driven neurodegeneration, and eCIRP inhibitors warrant investigation for both radiation-induced cognitive dysfunction and sporadic AD, where eCIRP is similarly elevated. Translating these mechanistic insights into eCIRP-targeted therapies and validated biomarkers could open a new front in the prevention and treatment of these prevalent and debilitating disorders.},
}

Humans
*Alzheimer Disease/epidemiology/metabolism/etiology/pathology
Animals
*Radiation, Ionizing
*RNA-Binding Proteins/metabolism
*tau Proteins/metabolism

@article {pmid42841310,
year = {2026},
author = {Pang, M and Brothers, HM and O'Gorman, J and Murphy, J and Zabar, Y and Lasky, T and Shen, C and Rubino, I and Knopman, D},
title = {Longitudinal clinical outcomes after amyloid clearance in aducanumab phase 3 studies.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71758},
pmid = {42841310},
issn = {1552-5279},
support = {//Biogen/ ; },
mesh = {Humans ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Double-Blind Method ; Female ; Male ; Treatment Outcome ; Positron-Emission Tomography ; Aged ; *Amyloid beta-Peptides/metabolism ; Longitudinal Studies ; *Amyloid/metabolism ; },
abstract = {INTRODUCTION: Anti-amyloid antibody clinical trials with a high proportion of participants reaching treatment-related amyloid clearance (TRAC) had positive clinical outcomes. We evaluated the aducanumab phase 3 program to determine whether TRAC during the double-blind period was likewise associated with clinical benefit.

METHODS: We pooled ENGAGE and EMERGE (E/E) aducanumab-treated participants in the amyloid positron emission tomography substudy who continued into the long-term extension ≤ 134 weeks (continuously treated population) and/or returned to the EMBARK redosing study 0.7 to 2.5 years after termination of E/E (treatment gap population). Clinical outcomes were stratified by week 78 TRAC status.

RESULTS: TRAC participants had less clinical decline at week 78, week 134, and EMBARK baseline than non-TRAC participants. Post-TRAC, clinical decline was heterogeneous; approximately two thirds of TRAC participants had annualized decline of < 1 point on Clinical Dementia Rating Sum of Boxes.

DISCUSSION: In these exploratory analyses, week 78 TRAC status was associated with better clinical outcomes.

CLINICAL TRIAL REGISTRATION: NCT02484547, NCT02477800, NCT04241068.},
}

Humans
*Antibodies, Monoclonal, Humanized/therapeutic use
*Alzheimer Disease/drug therapy/diagnostic imaging
Double-Blind Method
Female
Male
Treatment Outcome
Positron-Emission Tomography
Aged
*Amyloid beta-Peptides/metabolism
Longitudinal Studies
*Amyloid/metabolism

@article {pmid42841389,
year = {2026},
author = {Chapel, JM and Tysinger, B and Pourmand, H and Goldman, D and Aisen, P and , },
title = {The value of timely treatment with anti-amyloid therapy for Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71819},
pmid = {42841389},
issn = {1552-5279},
support = {U01AG086827/AG/NIA NIH HHS/United States ; //USC Schaeffer Center for Health Policy & Economics/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/economics ; Disease Progression ; Aged ; Female ; Treatment Delay ; Quality of Life ; United States ; Male ; Health Care Costs ; Cost-Benefit Analysis ; },
abstract = {INTRODUCTION: Anti-amyloid therapies can slow Alzheimer's disease (AD) progression; diagnostic and treatment delays might reduce their value.

METHODS: Using dynamic microsimulation, we estimated the gross societal value of anti-amyloid treatment for Americans with early symptomatic AD. A treatment scenario slowed the rate of clinical progression by 29% over individuals' remaining lifetime (baseline mean age: 73.0); earlier treatment initiated 2 years earlier.

RESULTS: Treatment generated $104,885 (95% CI: $99,291, $110,479) in gross societal value over an individual's lifetime, including quality-of-life gains, reduced caregiving burden, and medical cost offsets driven by reduced nursing home use and Medicaid spending. Earlier treatment increased value 32%; this rose to 71% if treatment effects are also stronger (36% slowing) in earlier AD stages. Scenarios with 4-year effect duration yielded $49,122 (treatment) and $56,385 (earlier treatment).

DISCUSSION: Timely treatment consistently increased long-term societal value. The findings provide a benchmark against which treatment implementation costs can be weighed.},
}

Humans
*Alzheimer Disease/drug therapy/economics
Disease Progression
Aged
Female
Treatment Delay
Quality of Life
United States
Male
Health Care Costs
Cost-Benefit Analysis

@article {pmid42841516,
year = {2026},
author = {Wu, D and Nie, MT and Lin, J and Liu, Y and Wang, Y and Chu, M and Zheng, L and Zhao, J},
title = {Rifaximin ameliorates memory impairment and Alzheimer's pathological changes in APP/PS1 mice associated with changes in the gut microbiome-bile acids-serum metabolites networks.},
journal = {British journal of pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1111/bph.70643},
pmid = {42841516},
issn = {1476-5381},
support = {2022MHPY02//Minhang Hospital of Fudan University/ ; 2025MHBJ03//Minhang Hospital of Fudan University/ ; MGWXK2023-04//Minhang Hospital of Fudan University/ ; 2024DR010//China University Industry-Academia-Research Innovation Fund/ ; },
abstract = {BACKGROUND AND PURPOSE: Modifying the brain-gut-microbiota axis has emerged as a promising therapeutic strategy against Alzheimer's disease (AD). Whether rifaximin, a non-absorbed and non-systemic antibiotic, can be applied to the treatment of AD remains unexplored. In this study, we investigated the effects of rifaximin using a APP/PS1 double-transgenic mouse model of AD.

EXPERIMENTAL APPROACH: Six-month-old male APP/PS1 mice were administered saline or rifaximin (100 mg·kg[-1]) via oral gavage for 2 months. Gut microbiota composition and metabolites were subsequently analysed to elucidate the underlying mechanisms of rifaximin in AD.

KEY RESULTS: Rifaximin modified gut microbiota composition, increasing abundance of Akkermansia muciniphila and Christensenellaceae, while decreasing abundance of Clostridia_UCG-014, Muribaculaceae, Lachnospiraceae, Turicibacter, Eubacterium_xylanophilum_group, Alistipes, Bacteroides_acidifaciens and Eubacterium_brachy groups. Furthermore, rifaximin alleviated memory impairment in APP/PS1 mice, decreased amyloid-β (Aβ) burden and secondary neuroinflammation and attenuated neuronal death and synaptic dysfunction. Metabolomic analysis revealed that rifaximin altered the profile of gut bile acids by decreasing the concentrations of primary (cholic acid and taurocholic acid) and secondary (taurodeoxycholic acid and taurolithocholic acid) bile acids. Additionally, rifaximin enhanced tryptophan metabolism, shown by increased serum 5-HT concentrations. Both microbial and metabolic shifts were closely correlated with gut microbiota composition.

CONCLUSIONS AND IMPLICATIONS: Our results showed that rifaximin alleviated spatial working and short-term recognition memory impairment and mitigated Alzheimer's-like pathological changes in APP/PS1 mice, effects accompanied by alterations in the gut microbiota-intestinal bile acid profile-serum metabolites network. Rifaximin could provide a new therapeutic approach to the treatment of AD.},
}

@article {pmid42831108,
year = {2026},
author = {Hung, KC and Yu, TS and Liu, PH and Lai, YC and Chen, IW},
title = {GLP-1 Receptor Agonists Versus DPP-4 Inhibitors and Incident Dementia Risk in COVID-19 Survivors with Type 2 Diabetes: A Target Trial Emulation Study.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {638249},
pmid = {42831108},
issn = {1177-8881},
mesh = {Humans ; *Diabetes Mellitus, Type 2/drug therapy ; *Glucagon-Like Peptide-1 Receptor Agonists ; *COVID-19/complications/epidemiology ; *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/adverse effects ; *Dementia/epidemiology ; *Hypoglycemic Agents/therapeutic use ; Male ; Female ; Aged ; Middle Aged ; Incidence ; Survivors ; },
abstract = {PURPOSE: Type 2 diabetes mellitus (T2DM) and COVID-19 are independently associated with an elevated risk of dementia, and COVID-19 survivors with T2DM may represent a clinically vulnerable population in whom metabolic, inflammatory, and vascular factors coexist. However, whether antidiabetic treatment choice is associated with incident dementia risk in this population remains unknown.

METHODS: In this target trial emulation using the TriNetX US Collaborative Network, we compared COVID-19 survivors aged ≥50 years with T2DM initiating glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy with those initiating dipeptidyl peptidase-4 inhibitor (DPP-4i) therapy between January 1, 2020 and December 31, 2024. We applied an active-comparator, new-user design with a 90-day survivor landmark and 1:1 propensity score matching. The primary outcome was incident all-cause dementia (a composite of vascular dementia, Alzheimer's disease, and other dementias). Secondary outcomes included dementia subtypes, mild cognitive impairment, glycemic outcomes, and all-cause mortality.

RESULTS: After matching, 25,263 patients per group were followed for up to 6 years (median, 919 days [GLP-1RA] vs 955 days [DPP-4i]). GLP-1RA initiation was associated with a lower hazard of incident dementia (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.58-0.72), vascular dementia (HR, 0.67; 95% CI, 0.52-0.85), and Alzheimer's disease (HR, 0.74; 95% CI, 0.59-0.93), as well as more favorable glycemic control and lower all-cause mortality (HR, 0.63; 95% CI, 0.59-0.68). The estimate for mild cognitive impairment was borderline (HR, 0.87; 95% CI, 0.75-1.00) and not consistently supported across sensitivity analyses. The association with incident dementia remained evident after the 6-month landmark analysis (HR, 0.66; 95% CI, 0.58-0.75) and was consistent across sensitivity and subgroup analyses.

CONCLUSION: Among COVID-19 survivors with T2DM, GLP-1RA initiation was associated with a lower hazard of incident dementia than DPP-4i initiation. These hypothesis-generating results warrant confirmation before they can be used to inform clinical decision-making.},
}

Humans
*Diabetes Mellitus, Type 2/drug therapy
*Glucagon-Like Peptide-1 Receptor Agonists
*COVID-19/complications/epidemiology
*Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/adverse effects
*Dementia/epidemiology
*Hypoglycemic Agents/therapeutic use
Male
Female
Aged
Middle Aged
Incidence
Survivors

@article {pmid42831322,
year = {2026},
author = {Xie, S and Zheng, B and Li, M and Zheng, B and Shen, G and Xiang, X and Chen, L},
title = {Sciadonic acid ameliorates cognitive impairment in APP/PS1 mice with concomitant modulation of gut microbiota and brain metabolism.},
journal = {Food & function},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6fo01986b},
pmid = {42831322},
issn = {2042-650X},
abstract = {Sciadonic acid (SCA) is a fatty acid derived from Torreya grandis oil with known anti-inflammatory and antioxidant properties; however, its role in Alzheimer's disease (AD) remains undefined. In this study, oral SCA administration to APP/PS1 transgenic mice significantly improved spatial learning and memory, as assessed by Morris water maze and Y-maze tests. Histological examination revealed reduced neuronal loss, preserved neuropil architecture, and diminished Aβ plaque burden in the hippocampus and cerebral cortex. SCA treatment enhanced antioxidant capacity, as indicated by elevated superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, alongside decreased malondialdehyde (MDA) and nitric oxide (NO) levels. Furthermore, SCA restored colonic mucosal integrity and suppressed pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Gut microbiota analysis revealed reversal of dysbiosis, with an increased Bacillota/Bacteroidetes ratio, enrichment of beneficial taxa such as Lactobacillus, and elevated short-chain fatty acid (SCFA) levels. Non-targeted hippocampal metabolomics identified modulation of 16 metabolites, predominantly in taurine and hypotaurine, and pyrimidine pathways. Collectively, SCA administration was associated with cognitive and neuropathological improvements alongside alterations in gut microbiota and hippocampal metabolism.},
}

@article {pmid42831987,
year = {2026},
author = {Ma, T and Zhou, H and Liu, Y and Cheng, X and Li, M},
title = {Electroacupuncture Targeting the NLRP3 Inflammasome in Senescence‑associated Cognitive Impairment: Mechanistic Synthesis and Meta‑analysis of Clinical Randomized Controlled Trials.},
journal = {Neurochemical research},
volume = {51},
number = {5},
pages = {},
pmid = {42831987},
issn = {1573-6903},
mesh = {Humans ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Electroacupuncture/methods ; *Inflammasomes/metabolism ; *Cognitive Dysfunction/therapy/metabolism ; Animals ; Randomized Controlled Trials as Topic/methods ; *Aging/metabolism ; },
abstract = {Global population aging leads to a growing clinical demand for interventions against age-related cognitive decline (ARCD), including mild cognitive impairment (MCI, termed senescence-associated cognitive impairment [SACI] in this review)-a prodromal pathological stage preceding Alzheimer's disease (AD) and vascular dementia. Chronic microglia-mediated neuroinflammation, predominantly triggered by excessive NLRP3 inflammasome activation, acts as a key upstream mediator of hippocampal neuronal injury and gradual cognitive decline in preclinical aging models.Manual acupuncture and electroacupuncture (EA) exert reproducible neuroprotective effects against cognitive deficits, yet a comprehensive, multi-layered regulatory framework unifying NLRP3-centered molecular mechanisms of acupuncture remains absent from current literature. This review systematically summarizes NLRP3‑dependent pathological cascades in SACI and outlines four synergistic signaling axes through which acupuncture may modulate excessive NLRP3‑dependent inflammatory responses to potentially alleviate neurotoxic inflammatory injury.Persistent overactivation of the NLRP3 inflammasome triggers self-amplifying inflammatory feedback cycles in hippocampal tissue through four interrelated pathological processes: impaired autophagic clearance, disrupted mitochondrial homeostasis, persistent endoplasmic reticulum (ER) stress, and caspase-1/GSDMD-mediated neuronal pyroptosis.Acupuncture counteracts NLRP3-dependent neural injury through synergistic multi-target modulation: (1) activation of AMPK/mTOR signaling to restore defective autophagy; (2) suppression of the ROS-TXNIP cascade to block NLRP3 transcriptional priming and protein oligomerization; (3) phenotypic reprogramming of microglia from pro-inflammatory M1 toward anti-inflammatory M2 states; (4) inhibition of pyroptotic execution by blunting caspase-1 maturation and GSDMD proteolytic cleavage. Collectively, available pre‑clinical evidence suggests these signaling axes constitute a bidirectionally‑interconnected hypothetical protective network that may mitigate chronic neuroinflammation.A meta analysis integrating nine eligible randomized controlled trials (published 2015-2025) involving 614 participants was performed. After subject dropout, 599 participants completed the studies. Pooled analyses of heterogeneous acupuncture/electroacupuncture RCTs revealed that intervention was associated with short‑term improvements in MoCA and MMSE scores and reduction in peripheral pro‑inflammatory cytokine IL‑6. Pooled effect sizes were moderately larger in MCI subgroups compared with patients with early AD. Nevertheless, substantial methodological heterogeneity existed across included trials, and these short term observational findings cannot confirm durable disease modifying benefits.Severe methodological heterogeneity across existing trials-including inconsistent acupoint prescriptions, divergent EA stimulation parameters, and variable treatment cycles-impairs cross-study comparability and translational reproducibility. Herein, we synthesize high‑quality preclinical and clinical evidence to propose a provisional consensus‑oriented translational reference protocol for electroacupuncture, intended for standardized mechanistic research rather than routine clinical intervention.Collectively, the NLRP3 inflammasome constitutes a tractable therapeutic target for acupuncture-mediated SACI intervention. Acupuncture exerts pleiotropic neuroprotection by dampening NLRP3-dependent neuroinflammation, alongside complementary NLRP3-independent regulatory pathways. This review‑meta‑analysis provides preliminary translational theoretical evidence for a provisional electroacupuncture intervention framework targeting NLRP3‑mediated neuroinflammation in MCI and early‑AD. Future high‑quality, multi‑center RCTs are warranted to validate these preliminary findings.},
}

Humans
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
*Electroacupuncture/methods
*Inflammasomes/metabolism
*Cognitive Dysfunction/therapy/metabolism
Animals
Randomized Controlled Trials as Topic/methods
*Aging/metabolism

@article {pmid42832237,
year = {2026},
author = {Estragués-Gázquez, I and Contador, J and Martínez, LD and Fernández-Lebrero, A and García-Escobar, G and Navalpotro-Gómez, I and Grau-Rivera, O and Iaccarino, G and Manero-Borràs, RM and Ortiz-Romero, P and Hernández-Villamizar, F and Torres-Torronteras, J and de Diego-Osaba, M and Blasco-Forniés, H and Jiménez-Moyano, E and Hernández, JJ and Padrós, A and Del Campo, M and Puig-Pijoan, A and Suárez-Calvet, M},
title = {Earlier Disclosure of Blood-Based Biomarkers, Diagnostic Certainty, and Clinical Management: A Randomized Clinical Trial.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
pmid = {42832237},
issn = {2168-6157},
abstract = {IMPORTANCE: Blood-based biomarkers show high performance for detecting Alzheimer disease (AD) pathology, but evidence on their impact on diagnostic certainty, clinical management, and emotional outcomes in routine care is limited.

OBJECTIVE: To determine whether earlier disclosure of plasma phosphorylated tau at threonine 217 (p-tau217) and neurofilament light chain (NfL) increases etiologic diagnostic certainty, influences clinical management, and affects emotional outcomes in individuals evaluated for cognitive symptoms.

This was a prospective randomized clinical trial conducted at a single memory clinic in Spain between February and October 2024, with 9 months of follow-up. Consecutive new outpatients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), or mild dementia without a prior etiologic diagnosis were enrolled. Of 265 eligible participants, 220 were randomized to earlier disclosure of blood-based biomarkers at the 3-month visit or delayed disclosure at the 9-month visit.

INTERVENTION: Disclosure of blood-based biomarkers for AD pathology (p-tau217) and neurodegeneration (NfL) to the treating neurologist and participant, alongside standard clinical evaluation.

MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of participants achieving a very high-confidence etiologic diagnosis (≥90%). Secondary outcomes included changes in clinical management and emotional outcomes (anxiety, depression, perceived stress, and quality of life).

RESULTS: Among the 220 randomized participants (median [IQR] age, 73 [68-78] years; 123 [55.9%] women), baseline diagnoses were SCD (100 [45.5%]), MCI (68 [30.9%]), and mild dementia (52 [23.6%]). At 3 months, a very high-confidence etiologic diagnosis was achieved in 56 of 112 participants in the earlier-disclosure arm (50.0%) compared with 5 of 108 in the delayed-disclosure arm (4.6%) (P < .001). Diagnostic certainty converged after disclosure in both arms, except among participants with MCI, in whom higher certainty persisted in the earlier-disclosure arm. Earlier disclosure was associated with more frequent initiation of symptomatic AD treatment (16/112 [14.3%] vs 5/108 [4.6%]; difference, 9.7; 95% CI, 1.8 to 17.8; P = .01), fewer planned follow-up neuropsychological reassessments for diagnostic clarification (34/112 [30.4%] vs 57/108 [52.8%]; difference, -22.4; 95% CI, -34.4 to -9.4; P < .001), and more planned discharge from the memory clinic to primary care (35/112 [31.3%] vs 13/108 [12.0%]; difference, 19.2; 95% CI, 8.4 to 29.5; P < .001). Earlier disclosure was not associated with worse emotional outcomes.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, earlier disclosure of blood-based biomarkers increased etiologic diagnostic certainty and led to earlier, targeted clinical management without increasing emotional distress. These findings support the integration of blood-based biomarkers into memory clinic diagnostic pathways.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06246019.},
}

@article {pmid42834737,
year = {2026},
author = {Marshall, JPS and Harutyunyan, A and Ng, J and West, OM and Collins, JM and King, AE and Morizzi, J and Wright, P and Calkin, AC and Drew, BG and Jones, NC and Adlard, PA and Febbraio, MA and Henstridge, DC},
title = {Genetic and Pharmacological Targeting of Hsp72 Overexpression/Induction in an Alzheimer's Disease Mouse Model With Combined Amyloid and Tau Pathology.},
journal = {Journal of neuroscience research},
volume = {104},
number = {10},
pages = {e70161},
pmid = {42834737},
issn = {1097-4547},
support = {//Yulgilbar Foundation/ ; //Dementia Australia Research Foundation/ ; //Shine on Foundation/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology/drug therapy ; *tau Proteins/metabolism ; Male ; Mice, Transgenic ; *HSP72 Heat-Shock Proteins/genetics/metabolism/biosynthesis ; Female ; Disease Models, Animal ; Mice ; *Amyloid beta-Peptides/metabolism ; Brain/metabolism/pathology ; Mice, Inbred C57BL ; },
abstract = {Heat shock protein 72 (Hsp72), a stress-inducible member of the Hsp70 family, has been implicated in mitigating the pathogenic effects of amyloid-beta (Aβ) and tau pathology; both key factors associated with the development and progression of Alzheimer's disease (AD). However, no in vivo study has been conducted to investigate the ability of Hsp72 to provide benefit when both Aβ and tau pathology are present concurrently. This study set out to utilize a genetic approach (transgenic overexpression) and a pharmacological validation approach (BGP-15) to increase Hsp72 expression in mice exhibiting Aβ and tau pathology (5xFADxTg30 model). Our findings indicate that genetic Hsp72 overexpression did not significantly alter Aβ or tau burden, deficits in motor performance, or alterations to body composition in this model, but modestly improved survival rates (driven by findings in male mice) and altered anxiety-like behavior (driven by findings in female mice). Similarly, BGP-15 treatment was unable to rescue behavioral traits, motor deficits, body composition, or alleviate Aβ or tau accumulation, although this treatment also showed a trend towards enhancing survival (again in male mice) and altered anxiety-like behavior (specifically in female mice). While the 5xFADxTg30 mice demonstrated seizure susceptibility compared to WT mice, BGP-15 was unable to alleviate this trait. These findings were independent of any measurable increase in Hsp72 abundance in the brain in response to BGP-15. Together, these findings suggest a limited impact of genetic overexpression and pharmacological targeting of Hsp72 protein abundance in this combined Aβ and tau model, although some sex-specific differences are noted.},
}

Animals
*Alzheimer Disease/metabolism/genetics/pathology/drug therapy
*tau Proteins/metabolism
Male
Mice, Transgenic
*HSP72 Heat-Shock Proteins/genetics/metabolism/biosynthesis
Female
Disease Models, Animal
Mice
*Amyloid beta-Peptides/metabolism
Brain/metabolism/pathology
Mice, Inbred C57BL

@article {pmid42834854,
year = {2026},
author = {Zhang, X and Xiong, YJ and Lv, T and Chen, Y},
title = {Trends in Population-Level Mortality Rates for Deaths With Both Alzheimer's Disease and Cancer Recorded on Death Certificates Among U.S. Adults Aged ≥ 65 Years, 1999-2023.},
journal = {Nursing open},
volume = {13},
number = {10},
pages = {e70897},
pmid = {42834854},
issn = {2054-1058},
support = {2025HY1587//Zhejiang Provincial Health Industry Science and Technology Program/ ; },
mesh = {Humans ; *Death Certificates ; Aged ; *Alzheimer Disease/mortality ; United States/epidemiology ; Female ; Male ; *Neoplasms/mortality ; Aged, 80 and over ; Cause of Death/trends ; *Mortality/trends ; },
abstract = {AIM: To examine temporal trends and demographic and geographic variation in population-level rates of deaths with both Alzheimer's disease (AD) and cancer recorded on death certificates among U.S. adults aged ≥ 65 years from 1999 to 2023.

DESIGN: A population-based descriptive time-trend study using multiple-cause-of-death data.

DATA SOURCES: National mortality data from the CDC WONDER (1999-2023).

REVIEW METHODS: Death certificates for U.S. residents aged ≥ 65 years recording both AD (G30) and malignant neoplasms (C00-C97) were included. Age-adjusted mortality rates (AAMRs) were standardized to the 2000 U.S. population; age-group analyses used age-specific crude mortality rates. Joinpoint regression estimated annual percent changes (APCs) and average annual percent changes (AAPCs), with analyses stratified by demographic and geographic characteristics.

RESULTS: Annual deaths increased from 4764 in 1999 to 6240 in 2023, while the overall AAMR declined from 13.96 to 12.05 per 100,000 (AAPC -0.73%, 95% CI -1.39 to -0.06). Significant declines occurred among males, adults aged 75 -84 years, non-Hispanic Black populations, and residents of the Northeast and Midwest, whereas a significant increase occurred among Hispanic populations. Full-period trends among females and non-Hispanic Other populations were not statistically significant. Neither metropolitan nor nonmetropolitan areas showed a significant trend during 1999-2020.

CONCLUSION: The overall age-adjusted death-certificate mortality rate declined modestly despite increasing annual death counts, with descriptive variation across demographic and geographic groups.

The findings highlight the relevance of coordinated geriatric and oncology nursing assessment and care planning for older adults with complex health needs. Nurses may play an important role in identifying cognitive, functional, treatment-related, and caregiver needs and facilitating multidisciplinary care. These descriptive findings identify areas for clinical attention but do not demonstrate the effectiveness of specific nursing interventions. WHAT PROBLEM DID THE STUDY ADDRESS?: Limited evidence exists on long-term population-level trends in deaths with both AD and cancer recorded on death certificates. WHAT WERE THE MAIN FINDINGS?: The overall age-adjusted mortality rate declined modestly while annual death counts increased. Subgroup-specific trends varied, but no formal between-group comparisons were performed. WHERE AND ON WHOM WILL THE RESEARCH HAVE AN IMPACT?: The findings are relevant to clinicians, policymakers, and public health practitioners involved in the care of older adults with multimorbidity, particularly in underserved populations.

REPORTING METHOD: This study adheres to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines.

No Patient or Public Contribution. This study used publicly available, de-identified mortality data and did not involve direct patient or public participation.},
}

Humans
*Death Certificates
Aged
*Alzheimer Disease/mortality
United States/epidemiology
Female
Male
*Neoplasms/mortality
Aged, 80 and over
Cause of Death/trends
*Mortality/trends

@article {pmid42835365,
year = {2026},
author = {Shan, SY and Bai, JM and Tian, Y and Shen, YF and Zhang, YX and Cheng, YH and Liu, Y and Ning, HY and Min, DY and Ren, L and Xiao, HH},
title = {Icariside II protects against neuronal injury by modulating PI3K/AKT-dependent mitochondrial dynamics and apoptosis in Alzheimer's disease models.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1911518},
pmid = {42835365},
issn = {1663-9812},
abstract = {INTRODUCTION: Icariside II (ICS II), a major bioactive flavonoid metabolite from Epimedium, has been reported to exert neuroprotective effects, but its role in regulating mitochondrial dysfunction-related neuronal injury in Alzheimer's disease (AD) has not been fully clarified.

METHODS: In this study, we administered ICS II to APP/PS1 transgenic mice and to two neuronal cell models of AD-like injury (Aβ-exposed HT22 cells and APP-overexpressing N2a cells). We evaluated cognitive behaviour, histopathological changes, Aβ burden, neuronal apoptosis, mitochondrial membrane potential (ΔΨm), mitochondrial reactive oxygen species (mtROS) levels, mitochondrial morphology and dynamics (including fragmentation, mitofusin-2 (Mfn2) expression, and dynamin-related protein 1 (Drp1) phosphorylation), as well as cytochrome c (Cyt c) release and caspase-3 activity. RNA-sequencing analysis of hippocampal tissue and pharmacological inhibition with the PI3K inhibitor LY294002 were employed to probe the involvement of the PI3K/AKT signalling pathway.

RESULTS AND DISCUSSION: In vivo, ICS II improved cognitive performance, ameliorated hippocampal and cortical histopathological damage, decreased Aβ immunoreactivity, and reduced neuronal apoptosis. RNA-sequencing analysis suggested the involvement of PI3K/AKT signaling in the response to ICS II treatment. In vitro, ICS II increased cell viability, reduced oxidative stress, and inhibited apoptosis. These effects were associated with increased PI3K expression and AKT phosphorylation, restoration of ΔΨm, reduced mtROS accumulation, restored mitochondrial morphology (e.g., alleviated fragmentation, reduced punctate fragments, and increased mitochondrial length), decreased Cyt c release, increased Mfn2 expression, and decreased Drp1 phosphorylation at Ser616 and caspase-3 levels. Notably, co-treatment with LY294002 largely abolished these protective effects, indicating that PI3K/AKT signaling is functionally involved in this process. Taken together, our findings suggest that ICS II protects against AD-related neuronal injury are closely associated with PI3K/AKT-dependent regulation of mitochondrial dynamics and apoptosis, thereby providing a mechanistic foundation for further exploration of ICS II as a natural product-derived candidate for AD intervention.},
}

@article {pmid42835402,
year = {2026},
author = {Zhang, R and Li, L and Tang, J and Hu, S and Zhang, Q and Tan, J},
title = {Ultrasound neuromodulation in brain disorders: from mechanotransduction mechanisms to clinical translation.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1942293},
pmid = {42835402},
issn = {1662-4548},
abstract = {Brain disorders impose a major global health burden, yet current pharmacological and neuromodulation therapies are often constrained by invasiveness, limited spatial precision, poor access to deep brain structures, or insufficient long-term efficacy. Non-invasive ultrasound neuromodulation has emerged as a promising approach combining high spatial resolution, deep tissue penetration, and reversible modulation. Its biological effects arise from multiscale mechanotransduction involving membrane deformation, mechanosensitive ion channels, intracellular calcium signaling, glial regulation, and neurovascular coupling. Together, these processes modulate neuronal excitability, synaptic plasticity, network connectivity, neuroinflammation, and cerebral perfusion. Preclinical studies support its therapeutic potential across neurological and psychiatric disorders, while early clinical studies indicate short-term tolerability and preliminary target engagement in Alzheimer's disease, Parkinson's disease, and depression. Emerging approaches, including individualized treatment planning, closed-loop stimulation, and sonogenetics, may further improve the precision and cellular specificity of ultrasound neuromodulation. This review summarizes the physical principles and cellular mechanisms of ultrasound neuromodulation, evaluates its therapeutic and clinical applications, and discusses key challenges and future directions, including personalized stimulation, closed-loop systems, sonogenetics, and disease-modifying strategies.},
}

@article {pmid42836463,
year = {2026},
author = {da Silva, JMA and Kümmerle, AE and Rodrigues, DA and Bolognesi, ML and Milelli, A and Lima, LM and de Sena Murteira Pinheiro, P},
title = {Recent advances of GPR40 agonists as potential anti-Alzheimer's agents.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/17568919.2026.2732260},
pmid = {42836463},
issn = {1756-8927},
abstract = {Alzheimer's disease (AD) is a progressive and multifactorial neurodegenerative disorder involving metabolic dysfunction, neuroinflammation, mitochondrial impairment, synaptic failure, and neuronal loss. Although amyloid-beta deposition and neurofibrillary tangles composed of hyperphosphorylated tau remain central pathological hallmarks, interconnected mechanisms contribute to disease progression and limit the effectiveness of single-target therapies. Current small-molecule drugs mainly provide symptomatic relief, whereas recently approved monoclonal antibodies have broadened the therapeutic landscape but still show modest clinical benefits, high treatment costs, and relevant safety concerns. GPR40/FFAR1, a transmembrane lipid-sensing G protein-coupled receptor, has emerged as a promising target because its activation may modulate neurotrophic signaling, neurogenesis, inflammatory regulation, neuronal survival, mitochondrial protection, autophagy, and synaptic plasticity. Preclinical studies suggest that GPR40/FFAR1 activation improves cognitive performance and attenuates AD-related pathological events through CREB activation, increased neurotrophic factor expression, reduced oxidative stress, restoration of autophagic flux, and inhibition of neuroinflammatory pathways, including NLRP3 inflammasome signaling. This review discusses the biological basis, pharmacological evidence, and medicinal chemistry advances supporting GPR40/FFAR1 as a potential therapeutic target for AD, while highlighting translational challenges related to selectivity, brain penetration, long-term safety, and target engagement.},
}

@article {pmid42836668,
year = {2026},
author = {Aboseif, A and Cacciaguerra, L and Vilaseca, A and Kondrakunta, S and Paramasivan, NK and Stabile, A and Patil, A and Li, X and Sarker, P and Christenson, LR and Brinkmann, B and Schwarz, CG and Kantarci, K and McKeon, A and Zekeridou, A and Basso, MR and Wingerchuk, DM and Irani, SR and Pittock, SJ and Zeydan, B and Dubey, D},
title = {Selective Limbic and Striatal Atrophy Corresponds to Regional Gene Expression in Leucine-Rich Glioma-Inactivated-1 Immunoglobulin G Autoimmune Encephalitis.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78389},
pmid = {42836668},
issn = {1531-8249},
abstract = {OBJECTIVE: To characterize regional brain atrophy patterns, evaluate their association with regional leucine-rich glioma-inactivated-1 (LGI1) gene expression, and identify clinical predictors of hippocampal atrophy in LGI1 autoimmune encephalitis (AE).

METHODS: This study compared regional brain volumes in LGI1-AE patients versus age- and sex-matched healthy controls (HC) and Alzheimer's disease (AD) patients. LGI1 gene expression was derived from the Allen Human Brain Atlas. Multivariable linear regression and generalized linear models were utilized.

RESULTS: A total of 55 LGI1-AE patients were included. Median age was 68 years (IQR 62.5-74.2 years) at volumetric analysis, after 19 months (IQR 11-45 months) from symptom onset. Compared with HC (n = 55) and AD patients (n = 55), LGI1-AE patients had greater regional atrophy of the hippocampus, insula, caudate, and putamen (p < 0.002). Longitudinal analyses demonstrated hippocampal and pallidal atrophy after covariate adjustment. Among those who did not fulfill limbic encephalitis criteria and/or had non-lesional magnetic resonance imaging, limbic and striatal atrophy were identified compared with HC (p < 0.01). Regions with the greatest differential atrophy corresponded to higher LGI1 gene expression (Spearman ρ = 0.7, p = 0.005). Severe cognitive deficits at diagnosis (β = -0.56; p = 0.002) and longer disease duration (β = -0.01; p = 0.001) independently predicted total hippocampal volume (R[2] = 0.31).

INTERPRETATION: LGI1-AE demonstrates a distinct pattern of limbic and striatal atrophy that differs from AD and aligns with regional LGI1 expression, supporting a model of selective network vulnerability. Greater baseline cognitive impairment and longer disease duration independently associated with hippocampal atrophy, underscoring the potential importance of early diagnosis and treatment to limit structural brain injury. ANN NEUROL 2026.},
}

@article {pmid42836738,
year = {2026},
author = {Sahelijo, N and Rajagopalan, P and Qian, L and Rahman, R and Goldstein, D and Thomopoulos, SI and Bennett, DA and Farrer, LA and Stein, TD and Shen, L and Huang, H and Nho, K and Saykin, AJ and Davatzikos, C and Thompson, PM and Tcw, J and Jun, GR},
title = {Cell-based polygenic risk scores predict clinical progression and prioritize network-based therapeutic targets in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71895},
pmid = {42836738},
issn = {1552-5279},
support = {/AG/NIA NIH HHS/United States ; R01-AG069453//National Institutes of Health (NIH)/ ; R01-AG082046//National Institutes of Health (NIH)/ ; U01-AG068057//National Institutes of Health (NIH)/ ; U01-AG082665//National Institutes of Health (NIH)/ ; U19-AG079774//National Institutes of Health (NIH)/ ; P30-AG072978//National Institutes of Health (NIH)/ ; U19-AG068753//National Institutes of Health (NIH)/ ; R01-AG082362//National Institutes of Health (NIH)/ ; R01-AG083941//National Institutes of Health (NIH)/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology ; Genetic Risk Score ; Disease Progression ; Female ; Apolipoproteins E/genetics ; Male ; Aged ; Astrocytes/metabolism ; Induced Pluripotent Stem Cells ; Genetic Predisposition to Disease ; },
abstract = {BACKGROUND: Late-onset Alzheimer's disease (AD) exhibits substantial biological heterogeneity. We developed a framework linking cell-type-specific polygenic risk profiles to precision medicine in AD.

METHODS: Cell-based polygenic risk scores (cbPRSs) derived from single-nucleus RNA-seq co-expression networks were evaluated in Alzheimer's Disease Neuroimaging Initiative (ADNI) and Framingham Heart Study (FHS) cohorts. Network hubs were prioritized using a graph-based PageRank algorithm and candidate drugs were validated in human-induced pluripotent stem cell (hiPSC)-derived astrocytes.

RESULTS: Cell-based PRS analysis identified two genetic risk axes independent of network cell-type labels: an apolipoprotein E (APOE)-concentrated axis (Ast-M2/Oli-M45) and an APOE-independent axis (Ast-M10/Oli-M50), which predicted accelerated progression to AD (hazard ratio: 1.25-2.02) and correlated with localized temporal lobe atrophy, reduced glucose metabolism, and global amyloid burden. High-risk status specifically upregulated complement C4a protein expression in postmortem brains. PageRank network analysis identified four candidate drugs targeting the APOE-containing astrocyte network. Experimental treatment with estradiol and levetiracetam significantly reduced APOE and complement C4 gene expression in hiPSC-derived astrocytes.

DISCUSSION: By integrating cell-based genetic risk with network-level target prioritization, this framework enables robust patient stratification and experimental target validation.},
}

Humans
*Alzheimer Disease/genetics/pathology
Genetic Risk Score
Disease Progression
Female
Apolipoproteins E/genetics
Male
Aged
Astrocytes/metabolism
Induced Pluripotent Stem Cells
Genetic Predisposition to Disease

@article {pmid42837119,
year = {2026},
author = {Klachacz, A and Malik, A},
title = {[Potential role of CHI3L1 in ischemic stroke - a neuroinflammatory or neuroprotective factor?].},
journal = {Postepy biochemii},
volume = {72},
number = {3},
pages = {201-210},
doi = {10.18388/wht2rw10},
pmid = {42837119},
issn = {0032-5422},
mesh = {Humans ; *Chitinase-3-Like Protein 1/metabolism/physiology ; Animals ; *Ischemic Stroke/metabolism/physiopathology ; Neuroprotective Agents/metabolism ; Signal Transduction ; *Brain Ischemia/metabolism ; *Neuroinflammatory Diseases/metabolism ; *Stroke/metabolism ; },
abstract = {Ischemic stroke is one of the leading causes of disability and death among adults worldwide. It occurs when blood flow to the brain is interrupted. Currently available treatments for patients with ischemic stroke focus solely on restoring blood flow. Therefore, there is a lack of methods that would accelerate brain regeneration after a stroke or even provide a protective effect. This study describes the role of the astrocyte-secreted protein CHI3L1 (chitinase-3-like protein 1) in the pathophysiology of stroke, as well as other diseases of the central nervous system. The structure of the protein, the receptors to which CHI3L1 binds and the activated signaling pathways along with the resulting biological effects relevant to ischemic stroke are discussed. It is indicated that changes in CHI3L1 levels potentially influence post-stroke regeneration in both humans and animal models. The common mechanisms of CHI3L1 action across various neurological diseases suggest its significant role in the future diagnosis and treatment of ischemic stroke, Alzheimer’s and Parkinson’s diseases, and glioma.},
}

Humans
*Chitinase-3-Like Protein 1/metabolism/physiology
Animals
*Ischemic Stroke/metabolism/physiopathology
Neuroprotective Agents/metabolism
Signal Transduction
*Brain Ischemia/metabolism
*Neuroinflammatory Diseases/metabolism
*Stroke/metabolism

@article {pmid42824090,
year = {2026},
author = {Schwartz, NU and Ellingson, T and Nguyen, H and Lin, Z and Ashton, NJ and Dage, JL and Deniz, K and Dietz, CD and Ljubenkov, PA and Miller, BL and Nael, K and Possin, K and Rojas, JC and Rosen, HJ and Saloner, R and Soleimani-Meigooni, DN and Staffaroni, AM and Stephens, ML and Tammewar, G and Wang, Y and La Joie, R and Rabinovici, GD and Boxer, AL and VandeVrede, L},
title = {Evaluation of plasma neurofilament and glial fibrillary acidic protein to predict or detect amyloid related imaging abnormalities.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70446},
pmid = {42824090},
issn = {2352-8729},
support = {K23 AG073514/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; T32 AG023481/AG/NIA NIH HHS/United States ; },
abstract = {INTRODUCTION: Amyloid-targeting therapies (ATT) require frequent magnetic resonance imaging monitoring to detect vasogenic edema and hemorrhage, i.e., amyloid-related imaging abnormalities (ARIA). Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are potential blood-based biomarkers (BBM) of ARIA.

METHODS: Plasma NfL and GFAP were longitudinally collected in an ATT clinic and natural log transformed. Baseline, pre-ARIA, and trajectories were compared between patients with (N = 15) and without (N = 45) ARIA.

RESULTS: Baseline NfL and GFAP did not differ between patients with or without ARIA (ln[NfL] ECLIA 1.24 ± 0.38 pg/mL vs 1.25 ± 0.40 pg/mL, p = 0.77; ln[NfL] Simoa 2.87 ± 0.47 pg/mL vs 2.98 ± 0.40 pg/mL, p = 0.30, ln[GFAP] ECLIA 4.95 ± 0.36 pg/mL vs 4.88 ± 0.47 pg/mL, p = 0.69). No significant changes were seen at the timepoint preceding ARIA, and ARIA incidence made no detectable impact on biomarker trajectories.

DISCUSSION: Biobanking in treatment clinics can evaluate clinical utility of BBMs as monitoring tools. These findings do not support a strong association between NfL or GFAP and ARIA in the ATT clinic.},
}

@article {pmid42825454,
year = {2026},
author = {Varshney, H and Siddique, YH},
title = {Molecular and genetic basis of alzheimer's disease and emerging treatment Modalities.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-21},
doi = {10.1080/17582024.2026.2739332},
pmid = {42825454},
issn = {1758-2032},
abstract = {BACKGROUND: Alzheimer's disease (AD) is linked to various causes and pathological processes. It represents a major global health challenge due to its increasing prevalence in aging populations. AD involves multifactorial pathological mechanisms. Two different forms of AD defined by changes in specific genes like APOE4, CLU, TREM2, PICALM, BIN1, MS4A, CR1, ABCA7 and APH1B. Apart from specific genetic mutations, there are multiple risk factors such as aging, obesity, lifestyle, head injury, drinking, smoking and environmental factors that further influence disease risk and its progression.

METHODS: The literature of this review article was taken from different search engines viz. Pubmed, Google Scholar and Scopus, explaining modifiable contributing factors and prognostic markers, including the genetics of AD and overall, this review analyzes literature published between 2000 to 2025 to summarizes the current status of disease, highlighting its importance for improving diagnosis, prognosis, and the development of targeted therapeutic strategies.

RESULT: There are multiple contributing factors in both the disease mechanism and development of AD, apart from amyloid hypothesis and neurofibrillary tangles.

DISCUSSION: A strategic analysis and targeted treatment of these contributing factors could help mitigate the progression of AD and offer potential protective benefits.},
}

@article {pmid42825521,
year = {2026},
author = {Nicol, NI and Li, T and Su, Q and Suhocki, A and Dunlap, E and Zhou, X and Jester, HM and Swift, NA and Underwood, E and Lee, J and Cervera-Juanes, R and Ma, T},
title = {AMPK Activator MK-8722 Improves Spatial Memory Deficit and Alters Metabolome in APP/PS1 AD Mouse Model.},
journal = {Journal of neurochemistry},
volume = {170},
number = {10},
pages = {e70563},
doi = {10.1111/jnc.70563},
pmid = {42825521},
issn = {1471-4159},
support = {R01 AG073823/AG/NIA NIH HHS/United States ; R01 AG082388/AG/NIA NIH HHS/United States ; RF1 AG082388/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/genetics ; *Metabolome/drug effects/physiology ; Mice ; Mice, Transgenic ; *AMP-Activated Protein Kinases/metabolism ; Presenilin-1/genetics ; *Amyloid beta-Protein Precursor/genetics ; *Memory Disorders/drug therapy/metabolism/genetics ; Disease Models, Animal ; Male ; Hippocampus/drug effects/metabolism ; *Spatial Memory/drug effects/physiology ; },
abstract = {Alzheimer's disease (AD) involves early synaptic vulnerability and systemic metabolic dysfunction, yet the impact of peripheral metabolic state on brain function remains unclear. Previous studies indicate a link between AMP-activated protein kinase (AMPK) signaling dysregulation and AD pathophysiology. Here we tested whether systemic treatment of a potent pan-AMPK activator MK-8722 influences cognitive function, synaptic plasticity, and circulating metabolic profiles in APP/PS1 AD model mice at the age of 6-8 months. MK-8722 was well tolerated and activated AMPK in the liver but not in the hippocampus. Our findings revealed that MK-8722 selectively improved AD-associated hippocampal-dependent spatial memory deficits and enhanced dendritic spine maturation in the hippocampus of APP/PS1 mice. In contrast, MK-8722 did not alter hippocampal long-term potentiation (LTP). In-depth analysis of plasma lipidomics and metabolomics revealed coordinated disruptions in glycerophosphatidylcholine species, glutathione cycling, carnitine-dependent fatty acid transport, and the kynurenine pathway in APP/PS1 mice, which were partially normalized by MK-8722 treatment. These findings suggest that peripheral AMPK activation can remodel systemic metabolic networks and improve certain aspects of cognitive and synaptic outcomes in early AD, supporting a model in which metabolic interventions outside the brain influence neuronal resilience.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/genetics
*Metabolome/drug effects/physiology
Mice
Mice, Transgenic
*AMP-Activated Protein Kinases/metabolism
Presenilin-1/genetics
*Amyloid beta-Protein Precursor/genetics
*Memory Disorders/drug therapy/metabolism/genetics
Disease Models, Animal
Male
Hippocampus/drug effects/metabolism
*Spatial Memory/drug effects/physiology

@article {pmid42825842,
year = {2026},
author = {Martinez Holst, MA and Sierra Valiente, AM and Garcia-Becerra, CA},
title = {Incidence, severity, and associated risk factors for amyloid-related imaging abnormalities in anti-amyloid monoclonal antibody therapy for early Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {10},
pages = {},
pmid = {42825842},
issn = {1590-3478},
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/epidemiology/genetics ; *Amyloid beta-Peptides ; *Antibodies, Monoclonal/therapeutic use ; Incidence ; Risk Factors ; },
abstract = {BACKGROUND: Amyloid-related imaging abnormalities (ARIA) are the most concerning side effect of the treatment for early Alzheimer's disease (AD) with anti-amyloid monoclonal antibodies (mAbs).

OBJECTIVE: This study systematically evaluates the incidence, severity, and associated risk factors of ARIA in patients with early AD receiving anti-amyloid mAbs therapy.

METHODS: A comprehensive systematic review and meta-analysis were conducted following PRISMA guidelines. Assessed outcomes included ARIA incidence, symptomatic cases and severity, radiographic severity, and risk factors. Pooled incidences and odds ratios were estimated with a random effects model using the R software (version 4.5.2).

RESULTS: The systematic search yielded a total of 20 articles, representing 21 phase 3 randomized controlled trials that involved 12,610 AD patients. Pooled incidence was 5.4% for ARIA-E and 10.27% for ARIA-H. Most cases being asymptomatic and radiographically mild to moderate. Risk factor analysis revealed that ApoE 4 homozygotes carriers (OR = 5.12), ApoE 4 heterozygotes carriers (OR = 1.91), higher mAb dosage (OR = 2.0) and baseline microhemorrhages (OR = 1.43) had a major influence on ARIA-E occurrence, as for ARIA-H incidence was higher in ApoE 4 heterozygous (OR = 1.65) and homozygotes carriers (OR = 4.65). Moreover, ApoE 4 heterozygous and homozygotic carriers were associated with symptomatic (OR = 1.52;3.68) and severe radiographic (OR = 2.11;6.31) ARIA-E.

DISCUSSION: ARIA remains a significant safety concern in anti-amyloid mAb therapy, with incidence and severity influenced by genetic, neuroimaging, and treatment-related factors. Future research should focus on refining risk stratification and understanding long-term consequences of ARIA.},
}

Humans
*Alzheimer Disease/drug therapy/diagnostic imaging/epidemiology/genetics
*Amyloid beta-Peptides
*Antibodies, Monoclonal/therapeutic use
Incidence
Risk Factors

@article {pmid42826598,
year = {2026},
author = {Rava, A and Di Trapano, M and Tse, C and Ji, L and Bid, HK and Trezza, V},
title = {Acidic cannabinoids in brain disorders: Neurobiological mechanisms, preclinical evidence, and translational challenges.},
journal = {Neuroscience and biobehavioral reviews},
volume = {191},
number = {},
pages = {107005},
doi = {10.1016/j.neubiorev.2026.107005},
pmid = {42826598},
issn = {1873-7528},
abstract = {Acidic cannabinoids, including tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), and related biosynthetic precursors, represent the predominant phytocannabinoid forms naturally produced by Cannabis sativa. Long considered pharmacologically inactive intermediates, these compounds are now increasingly recognized as bioactive molecules with potential therapeutic relevance for brain disorders. Compared with their decarboxylated counterparts, acidic cannabinoids exhibit distinct physicochemical, pharmacokinetic, and pharmacodynamic properties that may confer reduced psychotropic liability together with unique neurobiological effects. Emerging preclinical evidence indicates that acidic cannabinoids modulate multiple processes implicated in neurological and psychiatric disorders, including serotonergic and endocannabinoid signaling, neuroinflammation, oxidative stress, mitochondrial dysfunction, calcium dyshomeostasis, and synaptic transmission. In this review, we critically examine current knowledge regarding acidic cannabinoids in the context of brain disorders. We first summarize their biosynthesis, chemical stability, pharmacokinetic characteristics, and pharmacological differences from neutral cannabinoids. We then examine preclinical evidence supporting their potential therapeutic effects in epilepsy, anxiety, depression, psychosis-related conditions, and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We also discuss how artificial intelligence and computational approaches may support target identification, formulation optimization, pharmacokinetic modeling, and the development of personalized cannabinoid-based interventions. Finally, we highlight key methodological and translational challenges limiting the field and outline priorities for future research. Overall, acidic cannabinoids emerge as promising but still underexplored multitarget compounds with potential relevance for the treatment of brain disorders.},
}

@article {pmid42826681,
year = {2026},
author = {Xu, F and Li, H and Yan, Y and Chen, L and Sheng, Z and Dou, B and Yan, C and Zhu, X and Xu, Y},
title = {Cyclic nucleotide signaling through phosphodiesterase 1 inhibition and its interaction with the competing endogenous RNA network regulates cognition.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {204},
number = {},
pages = {119963},
doi = {10.1016/j.biopha.2026.119963},
pmid = {42826681},
issn = {1950-6007},
abstract = {BACKGROUND: Phosphodiesterase 1 (PDE1) has been demonstrated to be a potential drug target for a variety of diseases, ranging from peripheral system disease (PSD) to central nervous system disorders (CNSD). However, how cyclic nucleotide signaling, regulated by PDE1, particularly its isoform PDE1A, regulates the pathology of neurodegenerative disorders, including Alzheimer's disease (AD), remains unclarified.

METHOD: The Gene Expression Omnibus (GEO) database, a public gene expression repository, was used to analyze the role of PDE1 dysfunction in AD pathology. The mRNA and long non-coding RNA (lncRNA) were analyzed by comparing their differences in the GENCODE data resource V22. The relationship between PDE1, particularly PDE1A, and competing endogenous RNA (ceRNA) was validated by a dual-luciferase assay and reverse transcription-quantitative PCR (RT-qPCR), suggesting a potential ceRNA relationship among XIST, miR-338-3p, and PDE1A. Further cell-based assay and behavioral tests were conducted to determine the neuroprotective and memory-enhancing effects of PDE1 inhibition in cell and mouse models of AD.

RESULTS: A total of 11,781 differentially expressed genes (DEGs) were identified as AD- related genes. Approximately 1131 genes were identified as mitochondrial dysfunction-related by Venn plot analysis and were closely associated with AD pathology. PDE1, especially PDE1A, interacts with the lncRNA-microRNA network to promote cellular infiltration. These bioinformatic analyses were further supported by cell-based assays and behavioral studies, which demonstrated that treatment with the PDE1 inhibitor vinpocetine and PDE1A knockout ameliorated mitochondrial morphological abnormalities, restored immune function, and enhanced memory in a mouse model of AD.

CONCLUSION: These findings demonstrate that PDE1, particularly PDE1A activity, plays critical roles in AD progression by modulating mitochondrial morphology, immunity, and neuronal function, ultimately contributing to cognitive deficits.},
}

@article {pmid42828019,
year = {2026},
author = {Kucukbagriacik, Y and Saribas, GS and Ates, K and Ozturk, C and Kahyaoglu, E and Kislal, S and Akgul, CC and Karacalioglu, AO and Goksoy, C and Kantarcioglu, M},
title = {Exploratory effects of coffee-derived exosome-like nanoparticles in a fibrillar amyloid-beta 1-42-induced neurodegenerative rat model: evidence from fluorodeoxyglucose positron emission tomography and phosphorylated tau/amyloid precursor protein expression.},
journal = {PeerJ},
volume = {14},
number = {},
pages = {e21739},
pmid = {42828019},
issn = {2167-8359},
mesh = {Animals ; Male ; *Amyloid beta-Peptides/metabolism ; Rats, Sprague-Dawley ; *tau Proteins/metabolism ; *Nanoparticles/chemistry/administration & dosage ; *Exosomes/chemistry ; Peptide Fragments ; Rats ; Phosphorylation ; Disease Models, Animal ; *Coffee/chemistry ; Fluorodeoxyglucose F18 ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; *Amyloid beta-Protein Precursor/metabolism ; Positron-Emission Tomography ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta 1-42 (Aβ1-42) accumulation, tau pathology, and metabolic dysfunction. This exploratory study evaluated the effects of coffee-derived exosome-like nanoparticles (CELNs) on selected metabolic and histopathological endpoints in a fibrillar Aβ1-42-induced neurodegenerative rat model.

METHODS: Fifty male Sprague-Dawley rats were randomly divided into five groups (N = 10 each): Control (C), sham (SF), a fibrillar Aβ1-42-induced neurodegenerative rat model (AD), AD treated with a low dose of CELNs (AD + LE, 10 mg/kg/day), and AD treated with a high dose of CELNs (AD + HE, 20 mg/kg/day) for 14 days. CELNs were quantified and characterized using the bicinchoninic acid method, scanning electron microscopy, and nanoparticle tracking analysis (NTA). Micro-positron emission tomography/computed tomography fluorodeoxyglucose (MicroPET/CT FDG) imaging of the central nervous system was performed in all groups at the end of treatment. Subsequently, all animals were sacrificed, and hippocampal tissues were subjected to histopathological analysis.

RESULTS: MicroPET imaging demonstrated a significant, dose-dependent increase in cerebral glucose metabolism in AD rats treated with CELNs compared with the untreated AD group. Histopathological evaluations were consistent with the imaging data: in AD groups receiving CELNs, phospho-tau and beta-amyloid precursor protein expression were significantly reduced in the hippocampal cornu ammonis 2 (CA2) and dentate gyrus regions compared with the untreated AD group.

CONCLUSIONS: In this exploratory fibrillar Aβ1-42-induced neurodegenerative rat model, oral CELN administration was associated with dose-dependent partial improvements in cerebral glucose metabolism and region-specific reductions in hippocampal phosphorylated tau (p-Tau) and amyloid precursor protein (APP) immunoreactivity. However, these are preliminary biomarker-level findings that support further investigation of CELNs; definitive confirmation of functional and cognitive benefits requires additional behavioral, biodistribution, and experimental validation.},
}

Animals
Male
*Amyloid beta-Peptides/metabolism
Rats, Sprague-Dawley
*tau Proteins/metabolism
*Nanoparticles/chemistry/administration & dosage
*Exosomes/chemistry
Peptide Fragments
Rats
Phosphorylation
Disease Models, Animal
*Coffee/chemistry
Fluorodeoxyglucose F18
*Alzheimer Disease/drug therapy/diagnostic imaging/metabolism
*Amyloid beta-Protein Precursor/metabolism
Positron-Emission Tomography

@article {pmid42828568,
year = {2026},
author = {Bernetti, C and Calandrelli, R and Pilato, F and Di Lazzaro, V and Zobel, BB and D'Amelio, M and Mallio, CA},
title = {Exploring the role of glymphatic system in Alzheimer's disease with insights from MRI-based studies: a systematic review.},
journal = {Neuroradiology},
volume = {},
number = {},
pages = {},
pmid = {42828568},
issn = {1432-1920},
abstract = {BACKGROUND: The glymphatic constitutes a crucial neurophysiological mechanism for the clearance of interstitial solutes and neurotoxic metabolites from the central nervous system. Dysfunction within this pathway is increasingly implicated in the etiopathogenesis of neurodegenerative diseases, notably Alzheimer's disease (AD). Advanced magnetic resonance imaging (MRI) modalities, such as diffusion tensor image analysis along the perivascular space (DTI-ALPS), have emerged as non-invasive, in vivo approaches quantifying glymphatic transport efficacy and its association with cognitive decline and AD progression.

METHODS: This systematic review was conducted in adherence with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. and systematic literature retrieval was executed across PubMed, Cochrane, and Scopus databases, targeting studies that employed MRI-based metrics to assess glymphatic functionality in the context of AD.

RESULTS: A total of 35 studies fulfilled the inclusion criteria. AD patients exhibited significantly reduced DTI-ALPS indices, correlating with elevated enlarged perivascular space (ePVS) volumes, neurocognitive deterioration, and cerebral atrophy. Notably ePVSs enlargement emerged as a surrogate marker of glymphatic dysfunction and a predictor of MCI-to-AD conversion. However, amyloid PET correlations exhibited inter-study heterogeneity.

CONCLUSIONS: MRI derived biomarkers, particularly DTI-ALPS index and ePVSs analysis, demonstrate high potential as surrogate indicators of glymphatic impairment in AD. These findings underscore their diagnostic and prognostic value, warranting harmonization of imaging protocols and longitudinal investigations to establish their translational utility in clinical biomarker frameworks.

CLINICAL RELEVANCE STATEMENT: MRI biomarkers of glymphatic dysfunction provide valuable insights into Alzheimer's disease pathophysiology and progression. These imaging markers may enhance early diagnosis, monitor disease progression, and evaluate treatment efficacy in AD.},
}

@article {pmid42828605,
year = {2026},
author = {Przywara, D and Petniak, A and Gil-Kulik, P},
title = {The Therapeutic Potential of MicroRNAs Delivered By Mesenchymal Stem Cells in Parkinson's Disease, Alzheimer's Disease, and Stroke: A Systematic Review of Preclinical Studies.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42828605},
issn = {1559-1182},
mesh = {*MicroRNAs/administration & dosage/genetics/therapeutic use ; Animals ; Humans ; *Alzheimer Disease/therapy/genetics ; *Stroke/therapy/genetics ; *Mesenchymal Stem Cells/metabolism ; *Mesenchymal Stem Cell Transplantation/methods ; *Parkinson Disease/therapy/genetics ; },
abstract = {Population aging has led to a substantial increase in the prevalence of neurological disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), and stroke. As current therapeutic strategies are largely limited to symptomatic management, the identification of disease-modifying treatments remains a major unmet clinical need. Mesenchymal stem cells (MSCs) and MSCs-derived microRNAs (miRNAs) have emerged as promising therapeutic candidates for these conditions. A systematic literature search was conducted in the PubMed and Scopus databases in accordance with the PRISMA guidelines. The aim was to synthesize the available evidence regarding the effects of MSCs-derived miRNAs on cellular processes, including apoptosis, proliferation, inflammation, oxidative stress, and motor function in experimental models of PD, AD, and stroke. Risk of bias was assessed using the SYRCLE Risk of Bias tool for animal intervention studies and the modified OHAT Risk of Bias Rating Tool (mOHAT). A total of 37 preclinical studies were included in the review: 9 focused on PD, 10 on AD, and 18 on stroke. The synthesized evidence indicates that specific MSCs-derived miRNAs, particularly miR-133b, miR-146a, miR-17-92, and miR-223, exert significant neuroprotective effects. These miRNAs actively modulate gene expression, attenuate neuroinflammation and apoptosis, and reduce the accumulation of disease-specific pathological markers, including α-synuclein and amyloid-β (Aβ). Furthermore, targeted delivery of these miRNAs was associated with improved motor and cognitive outcomes across the evaluated animal models. MSCs-derived miRNAs demonstrate considerable therapeutic potential for the treatment of neurodegenerative diseases and stroke through the modulation of multiple pathological pathways. However, as the current evidence is derived exclusively from in vitro and animal studies, future research should focus on the development of safe, standardized, and reproducible protocols to facilitate the translation of these findings into human clinical trials. The review was registered in the Open Science Framework (OSF): https://osf.io/cxt9b .},
}

*MicroRNAs/administration & dosage/genetics/therapeutic use
Animals
Humans
*Alzheimer Disease/therapy/genetics
*Stroke/therapy/genetics
*Mesenchymal Stem Cells/metabolism
*Mesenchymal Stem Cell Transplantation/methods
*Parkinson Disease/therapy/genetics

@article {pmid42828695,
year = {2026},
author = {Inui, Y and Takechi, H and Watanabe, H and Kato, T and Ito, K and Kobayashi, R and Toyama, H and Inoue, M},
title = {Multimodal neuroimaging in dementia and neurodegenerative disorders: complementary roles of clinically available nuclear medicine and MRI in the era of disease-modifying therapies.},
journal = {Japanese journal of radiology},
volume = {},
number = {},
pages = {},
pmid = {42828695},
issn = {1867-108X},
abstract = {The introduction of anti-amyloid-β antibody therapies has fundamentally changed the clinical landscape of dementia, shifting the role of neuroimaging from diagnosis toward therapeutic decision-making. Amyloid positron emission tomography (PET) has become essential for confirming amyloid pathology and determining treatment eligibility. However, amyloid deposition is frequently observed in cognitively normal elderly individuals and in non-Alzheimer neurodegenerative disorders, indicating that amyloid status alone is insufficient to explain clinical symptoms. In this context, imaging modalities reflecting neurodegeneration, including structural magnetic resonance imaging (MRI) and functional imaging such as [18]F-FDG-PET and brain perfusion single-photon emission computed tomography (SPECT), remain important for assessing disease severity and functional impairment. Furthermore, discrepancies between imaging biomarkers-such as the presence of neurodegeneration without amyloid pathology in cases clinically suspected of Alzheimer's disease, and atypical imaging patterns-are commonly encountered in clinical practice and may reflect underlying pathological heterogeneity. A multimodal imaging approach that integrates multiple biomarkers provides complementary information and may improve diagnostic accuracy and clinical interpretation. In addition, other imaging modalities, including dopamine transporter (DAT) imaging and cardiac sympathetic imaging, can contribute to the evaluation of non-Alzheimer pathologies. This review summarizes the current roles of clinically available multimodal imaging in dementia, with a focus on nuclear medicine and MRI, highlighting their complementary value and clinical implications in the era of disease-modifying therapies.},
}

@article {pmid42828701,
year = {2026},
author = {Lei, Y and Luo, Y and Li, L},
title = {Collagen Triple Helix Repeat Containing 1 (CTHRC1) in the Nervous System: Expression, Signaling Mechanisms, and Functional Implications.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {4},
pages = {},
pmid = {42828701},
issn = {1559-1166},
support = {2024AAC03777//Natural Science Foundation of Ningxia Province/ ; },
mesh = {Animals ; Humans ; *Extracellular Matrix Proteins/metabolism/genetics ; *Signal Transduction ; },
abstract = {Collagen triple helix repeat containing 1 (CTHRC1) is a secreted extracellular matrix (ECM)-associated protein involved in tissue remodeling, fibrosis, and cancer, but its functions in the nervous system remain incompletely defined. Evidence from peripheral nerve, brain tumor, neurodegeneration, and regeneration models suggests that CTHRC1 may exert context-dependent effects across neural and stromal cell populations. In Schwann cells, CTHRC1 regulates proliferation, migration, and the timing of myelination, whereas in glioma it promotes invasive behavior and treatment-resistant phenotypes. Human cortical proteomics, mouse-model studies, systems genetics, and a neuronal cell model associate CTHRC1 with Alzheimer's disease-related phenotypes, although bulk tissue does not identify the cellular source and a small cerebrospinal fluid cohort showed no significant change. Temporally resolved single-cell analysis in zebrafish identified a transient cthrc1a-expressing fibroblast state required for coordinated inflammatory dynamics during regeneration; an equivalent mammalian mechanism has not been established. Evidence connecting CTHRC1 to synaptic regulation, neuroprotection, Parkinson's disease, and cerebrovascular repair is still preliminary. Wnt, TGF-β/Smad, PI3K/AKT, and MAPK/ERK pathways provide candidate mechanisms, but many were characterized outside normal neural cells. This review critically evaluates the evidence by model and cell type and discusses biomarker and therapeutic prospects, including delivery, specificity, and safety constraints.},
}

Animals
Humans
*Extracellular Matrix Proteins/metabolism/genetics
*Signal Transduction

@article {pmid42830424,
year = {2026},
author = {Chen, Y and Liu, Y and Xie, J and Wang, S and Zhou, D and Song, G and Dou, Y},
title = {A LIFU-responsive phase-change nanoplatform enhances hippocampal galantamine exposure and cognitive outcomes in APP/PS1 mice.},
journal = {Journal of biomaterials science. Polymer edition},
volume = {},
number = {},
pages = {1-23},
doi = {10.1080/09205063.2026.2741654},
pmid = {42830424},
issn = {1568-5624},
abstract = {Alzheimer's disease (AD) lacks spatiotemporally controllable strategies for drug delivery to deep brain targets. Galantamine (GTM) is clinically used for symptomatic management of AD, yet systemic dosing is constrained by peripheral adverse effects and limited, nonselective brain exposure. Here, we engineered a PEGylated phase-change liposomal nanoplatform co-loading GTM and perfluoropentane (PFP) (PEG-LIP@PFP@GTM) to integrate noninvasive nose-to-brain delivery with low-intensity focused ultrasound (LIFU)-assisted enhancement of GTM exposure in the hippocampal region. PEG-LIP@PFP@GTM showed a hydrodynamic diameter of 158.8 ± 1.6 nm with a PDI of 0.165 ± 0.017, an encapsulation efficiency of 69.26 ± 2.07%, and a drug loading content of 6.37 ± 0.65%. PFP endowed the formulation with thermo-responsive phase-transition behavior and LIFU-enhanced GTM release under physiological-temperature conditions. In vivo fluorescence imaging and ex vivo brain sectioning provided evidence of brain accessibility after intranasal administration, while also identifying 4 h post-dosing as a practical window for hippocampal LIFU irradiation. In APP/PS1 mice, compared with the non-irradiated nanoplatform group, phase-change liposomes combined with hippocampal LIFU irradiation significantly increased PSD95 fluorescence intensity (p = 0.0028) and improved Y-maze novel-arm time (p = 0.0003) and Morris water maze target-quadrant time (p = 0.0237), and significantly reduced the Aβ-positive area (p = 0.0461). Histological examination revealed no overt abnormalities in the nasal mucosa or major peripheral organs under the tested conditions. Collectively, these findings support combining intranasal nanocarrier delivery with externally applied hippocampal LIFU, with LIFU activation providing additional benefit beyond non-irradiated nanocarrier treatment under the tested conditions.},
}

@article {pmid42818885,
year = {2026},
author = {Kuik, EJ and Baena-Tan, C and Moriguchi, S and Braga, J and Miler, L and Rusjan, P and Bagby, M and Husain, MI and Vasdev, N and Tomoda, T and Banasr, M and Kloiber, S and Meyer, JH},
title = {Effects of sex, treatment resistance, and antidepressant treatment on monoamine oxidase B total distribution volume.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {42818885},
abstract = {Monoamine oxidase B (MAO-B) is a high-density protein located mainly in astrocytes that influences mitochondrial function and transition to astrogliosis. MAO-B produces hydrogen peroxide while metabolizing non-serotonergic monoamines. Elevated MAO-B level is implicated in the pathophysiology of several common neuropsychiatric diseases. The aims are to examine the effect of treatment resistant major depressive episodes, sex, and antidepressant treatment on MAO-B total distribution volume ([ [11] C]SL25.1188 V T), index of MAO-B level. [ [11] C]SL25.1188 PET was applied in 95 adults (29 with MDE and no history of treatment-resistance (NTR-MDE), 26 with MDE and history of treatment-resistance (TRD), and 40 healthy control (HC)). A subset of NTR-MDE and TRD (n=13) were scanned before and after treatment with phenelzine, rasagiline, or duloxetine. [ [11] C]SL25.1188 V T was higher in grey matter regions in females (10%, p <.001). [ [11] C]SL25.1188 V T was also higher in prefrontal cortex in TRD compared to HC (23%, p<.001) and TRD compared to NTR-MDE (6%, p =.033). Duloxetine had minimal effect on [ [11] C]SL25.1188 V T , but occupancy of rasagiline and phenelzine was ∼94%. This study discovered sex differences in MAO-B level, which may explain sex differences in prevalence or trajectory of illnesses with greater MAO-B level like Alzheimer's disease, traumatic brain injury and major depressive disorder. Given our findings of greater MAO-B level in prefrontal cortex of TRD and its insensitivity to serotonin reuptake inhibition, combined with potential harm of highly elevated MAO-B level, development of MAO-B inhibitors could be considered for a subset of TRD. Rasagiline and phenelzine demonstrate similarly potent occupancy in vivo at clinical dosage.},
}

@article {pmid42818911,
year = {2026},
author = {Han, S and Liu, F and Wang, D and Song, G},
title = {Aildenafil citrate with superior PDE5 selectivity ameliorates cognitive and behavioral impairments in APP/PS1 Alzheimer's disease mice: a preclinical phenotypic study.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1933588},
pmid = {42818911},
issn = {1663-9812},
abstract = {INTRODUCTION: Alzheimer's disease (AD) imposes a significant global healthcare burden, and current available pharmacotherapies provide limited therapeutic benefits. Disrupted phosphodiesterase 5 (PDE5) signaling has been implicated in the pathogenesis of AD and other neurodegenerative disorders, positioning PDE5 inhibitors (PDE5Is) as a promising therapeutic strategy for AD treatment. This study evaluated the preclinical therapeutic potential of aildenafil citrate (AC), a selective PDE5I approved in China for the treatment of erectile dysfunction (ED), in AD treatment.

METHODS: Molecular docking, molecular dynamics (MD) simulations, and MM-GBSA binding free energy calculations were integrated to explore the molecular mechanisms of aildenafil. The APP/PS1 transgenic mouse model of AD was employed to assess the in vivo efficacy of AC through behavioral, pathological, and oxidative assessments.

RESULTS: In silico analyses indicated that aildenafil exhibited a higher predicted affinity through a strengthened electrostatic network anchored by key bidentate hydrogen bonds with Gln817 and enhanced π-π stacking interactions with Phe820. Behavioral assessments, including the Barnes maze and Open field tests, demonstrated that AC significantly ameliorates cognitive dysfunction and anxiety-like impairments. Pathological examinations revealed improved hippocampal morphology, upregulated neprilysin (NEP) expression, and reduced Aβ accumulation. The decreased malondialdehyde (MDA) levels further suggested a potential attenuation of systemic oxidative stress and provided preliminary support for further investigation into its effects on central redox status.

CONCLUSION: These findings offer an initial phenotypic characterization of AC in an AD mouse model, underscoring the need for comprehensive mechanistic studies to fully evaluate its potential as a repurposed AD therapeutic candidate.},
}

@article {pmid42821606,
year = {2026},
author = {Xu, MY and Bai, YD and Zeng, XQ and Tan, CR and Lai, YJ and Wang, YJ},
title = {Bazedoxifene restores myelin changes and attenuates cognitive deficits in a mouse model of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261490479},
doi = {10.1177/13872877261490479},
pmid = {42821606},
issn = {1875-8908},
abstract = {BackgroundDemyelination and remyelination are critical processes in the pathogenesis of Alzheimer's disease (AD). The selective estrogen receptor modulator bazedoxifene (BZA) has been shown to promote remyelination, suggesting its potential therapeutic efficacy.ObjectiveThis study aimed to evaluate the therapeutic efficacy of BZA in addressing demyelination and associated cognitive deficits in a mouse model of AD.MethodsThe changes in myelin and oligodendrocyte-related indicators in the brains of APP/PS1 mice were assessed via immunostaining. 5 × FAD transgenic mice received oral administration of BZA or vehicle for 3 months. The therapeutic outcomes were evaluated through behavioral tests, immunostaining and western blotting.ResultsAD mice exhibited pronounced myelin loss and oligodendrocytes depletion. BZA treatment attenuated cognitive decline, restored myelin changes and mitigated neurodegeneration in the brain. These effects were observed independently of alterations in amyloid-β deposition.ConclusionsThese findings provide compelling evidence supporting the involvement of demyelination in AD and suggest that BZA may represent a promising therapeutic agent for AD by targeting myelin repair mechanisms.},
}

@article {pmid42821845,
year = {2026},
author = {Shir, D and Algeciras-Schimnich, A and Piura, YD and Bornhorst, JA and Figdore, DJ and Elgenidi, A and Lachner, C and Graff-Radford, NR and Day, GS},
title = {Clinical Factors Associated With Discordant Plasma P-Tau217 and Established Alzheimer Disease Biomarkers.},
journal = {Neurology},
volume = {107},
number = {8},
pages = {e218591},
pmid = {42821845},
issn = {1526-632X},
support = {R01 AG041851/AG/NIA NIH HHS/United States ; RF1 AG069052/AG/NIA NIH HHS/United States ; R01 AG089380/AG/NIA NIH HHS/United States ; R01 AG075802/AG/NIA NIH HHS/United States ; UF1 NS125417/NS/NINDS NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; R37 AG011378/AG/NIA NIH HHS/United States ; RF1 AG061900/AG/NIA NIH HHS/United States ; R01 AG056366/AG/NIA NIH HHS/United States ; UH2 AG083186/AG/NIA NIH HHS/United States ; U01 AG057195/AG/NIA NIH HHS/United States ; U01 NS120901/NS/NINDS NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; U19 AG032438/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *tau Proteins/blood ; *Alzheimer Disease/blood/diagnosis ; Female ; Biomarkers/blood ; Male ; Retrospective Studies ; Aged ; Amyloid beta-Peptides/cerebrospinal fluid/blood ; Aged, 80 and over ; Middle Aged ; Phosphorylation ; Positron-Emission Tomography ; },
abstract = {BACKGROUND AND OBJECTIVES: Plasma phosphorylated tau (p-tau) 217 is increasingly used for Alzheimer disease (AD) diagnosis and treatment decisions but may be discordant with established AD biomarkers. False-positive (FP) plasma results may lead to overtreatment and false-negative (FN) results to missed or delayed disease-modifying therapies. We evaluated factors associated with discordant results.

METHODS: This retrospective study included participants enrolled in memory and aging studies at Mayo Clinic with "positive" (>0.324 pg/mL) or "negative" (<0.186 pg/mL) plasma p-tau217 results and confirmatory AD biomarkers. Plasma results were classified as true positive (TP), true negative (TN), FP, or FN, referencing amyloid-PET and CSF p-tau181/β-amyloid (Aβ) 42. Clinical and laboratory variables were compared using univariate analyses; multivariable logistic regression evaluated independent associations with discordance.

RESULTS: Among 706 participants (median 70.0 [interquartile range 15.8] years; 54% male), 60 (8.5%) had discordant plasma p-tau217 results. FN results (5.6%) were more frequent than FP results (2.8%; p = 0.007). Discordance was associated with older age (odds ratio [OR] 1.61 per decade, 95% CI 1.23-2.14) and obstructive sleep apnea (OR 1.94, 95% CI 1.08-3.49). FN (vs TP) results were associated with milder clinical stage (global Clinical Dementia Rating [CDR] ≤0.5 vs CDR ≥1; p < 0.001), higher Mini-Mental State Examination scores (OR 1.20 per point, 95% CI 1.05-1.36), obstructive sleep apnea (OR 2.01, 95% CI 1.01-4.3), higher body mass index (OR 1.11/kg/m[2], 95% CI 1.03-1.20), and higher estimated glomerular filtration rate (eGFR: OR 1.33/10 mL/min/1.73 m[2], 95% CI 1.05-1.69). In age-adjusted models, body mass index (OR 1.14, 95% CI 1.03-1.25), eGFR (OR 1.63/10 mL/min/1.73 m[2], 95% CI 1.22-2.16), and earlier clinical stage (CDR ≤0.5) were independently associated with FN results. FP (vs TN) results were associated with older age (OR 2.37, 95% CI 1.36-4.09), thyroid disease (OR 4.41, 95% CI 1.36-14.3), lower eGFR (OR 0.48/10 mL/min/1.73 m[2], 95% CI 0.31-0.66), and advanced disease stage (CDR ≥1). In age-adjusted models, eGFR (OR 0.54/10 mL/min/1.73 m[2], 95% CI 0.35-0.82) and advanced disease stage (CDR ≥ 1 vs CDR 0: OR 11.11, 95% CI 2.0-50.0; vs CDR 0.5: OR 4.55, 95% CI 1.12-16.67) were independently associated with FP results.

DISCUSSION: Plasma p-tau217 results and established AD biomarkers were discordant in 8.5% of participants. Clinical stage and factors related to brain amyloid clearance, renal clearance, and volume of distribution were associated with discordant results. These insights may inform mechanisms of discordance and identify patients requiring confirmatory biomarker measures.},
}

Humans
*tau Proteins/blood
*Alzheimer Disease/blood/diagnosis
Female
Biomarkers/blood
Male
Retrospective Studies
Aged
Amyloid beta-Peptides/cerebrospinal fluid/blood
Aged, 80 and over
Middle Aged
Phosphorylation
Positron-Emission Tomography